fphar-13-935536

TYPE Review
PUBLISHED 22 July 2022

DOI 10.3389/fphar.2022.935536
Connections between
OPEN ACCESS metabolism and epigenetics:
EDITED BY
Na Li,
University of California, San Diego,
mechanisms and novel
United States
REVIEWED BY
anti-cancer strategy
Xiawei Cheng,
East China University of Science and
Technology, China
Chen Chen†, Zehua Wang† and Yanru Qin*
Vera Miranda-Gonçalves,
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Portuguese Oncology Institute,
Portugal
*CORRESPONDENCE
Yanru Qin,
yanruqin@163.com Cancer cells undergo metabolic adaptations to sustain their growth and
†
These authors have contributed equally proliferation under several stress conditions thereby displaying metabolic
to this work and share first authorship plasticity. Epigenetic modification is known to occur at the DNA, histone,
SPECIALTY SECTION and RNA level, which can alter chromatin state. For almost a century, our
This article was submitted to focus in cancer biology is dominated by oncogenic mutations. Until recently,
Pharmacology of Anti-Cancer Drugs,
a section of the journal the connection between metabolism and epigenetics in a reciprocal manner
Frontiers in Pharmacology was spotlighted. Explicitly, several metabolites serve as substrates and co-
RECEIVED 04 May 2022 factors of epigenetic enzymes to carry out post-translational modifications
ACCEPTED 29 June 2022 of DNA and histone. Genetic mutations in metabolic enzymes facilitate the
PUBLISHED 22 July 2022
production of oncometabolites that ultimately impact epigenetics. Numerous
CITATION
evidences also indicate epigenome is sensitive to cancer metabolism.
Chen C, Wang Z and Qin Y (2022),
Connections between metabolism and Conversely, epigenetic dysfunction is certified to alter metabolic enzymes
epigenetics: mechanisms and novel leading to tumorigenesis. Further, the bidirectional relationship between
anti-cancer strategy.
Front. Pharmacol. 13:935536. epigenetics and metabolism can impact directly and indirectly on immune
doi: 10.3389/fphar.2022.935536 microenvironment, which might create a new avenue for drug discovery. Here
COPYRIGHT we summarize the effects of metabolism reprogramming on epigenetic
© 2022 Chen, Wang and Qin. This is an modification, and vice versa; and the latest advances in targeting
open-access article distributed under
the terms of the Creative Commons
metabolism-epigenetic crosstalk. We also discuss the principles linking
Attribution License (CC BY). The use, cancer metabolism, epigenetics and immunity, and seek optimal
distribution or reproduction in other immunotherapy-based combinations.
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the KEYWORDS
original publication in this journal is
cited, in accordance with accepted cancer metabolism, epigenetics, immunity, novel anti-cancer strategy, oncology
academic practice. No use, distribution
or reproduction is permitted which does
not comply with these terms. 1 Introduction
Cancer metabolism is based on the principle that cancer cells undergo metabolic
adaptations to sustain their uncontrolled proliferation. Such adaptations render malignant
cells to exhibit altered metabolism compared to the normal cells. In 1920s, Warburg firstly
proposed (Kaye, 1998; Chinnaiyan et al., 2012) that cancer cells display enhanced glycolysis and
increased secretion of lactate even with abundant oxygen supply. This phenomenon is termed
as “Warburg effect” or aerobic glycolysis. Moreover, an emerging class of metabolic alterations
enables tumor cells to take up available ample nutrients and utilize them to produce ATP,
generate biosynthetic precursors for cell anabolism, and tolerate stresses related to malignancy,
Frontiers in Pharmacology 01 frontiersin.org

Chen et al. 10.3389/fphar.2022.935536
FIGURE 1
Metabolism reprogramming in cancer cells. Metabolism reprogramming is characterized by a class of altered pathway, including enhanced
glycolysis with increased lactate production, and enhanced pentose phosphate pathway, fatty acid synthesis, and glutamine metabolism. These
metabolic pathways support energy supply and macromolecule biosynthesis, such as nucleotides, amino acids, and lipids. Metabolites that are
produced by altered metabolism have the potential to control signaling or epigenetic pathways by regulating reactive oxygen species,
acetylation, and methylation. Upregulated genes or proteins are labels red, whereas downregulated genes or proteins are labeled blue. GLUT,
glucose transporter; MCT, monocarboxylate transporter; SLC1A5, solute carrier family 1 member 5; TCA, Tricarboxylic acid cycle; G6PD, glucose-6-
phosphate dehydrogenase; HK, hexokinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PKM, pyruvate kinase M 2; LDH, lactate
dehydrogenase; ACSS2, Acyl-CoA short-chain synthetase-2; ACSS1: Acyl-CoA short-chain synthetase-1; ACLY: ATP citrate lyase; GLS, glutaminase;
GDH, glutamate dehydrogenase; PDC: pyruvate dehydrogenase complex; FH, fumarate hydratase; SDH, succinate dehydrogenase; IDH1/2,
isocitrate dehydrogenase 1/2; HCY, homocysteine; PPP, pentose phosphate pathway; ATP, adenosine triphosphate; ADP, adenosine diphosphate;
AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; OGT, O-GlcNAc transferase; OGA, O-GlcNAcase.
such as hypoxia and nutrient starvation (Owen et al., 2002; Koppenol (Ribich et al., 2017). Numerous excellent reviews have
et al., 2011; Lunt and Vander Heiden, 2011; Metallo et al., 2011; summarized the biology fundamentals of chromatin-modified
Mullen et al., 2011; Wise et al., 2011; Cantor and Sabatini, 2012; Ahn proteins (CMPs) (Tessarz and Kouzarides, 2014; Piunti and
and Metallo, 2015). In this context, cancer metabolism provides a Shilatifard, 2016; Soshnev et al., 2016) and the therapeutic
selective advantage during tumorigenesis. Metabolic reprogramming potentials to target CMPs in tumor (Pfister and Ashworth, 2017).
(Figure 1) is now recognized as a hallmark of cancer (Hanahan and For almost a century, our focus in cancer is dominated by
Weinberg, 2011; Pavlova and Thompson, 2016), which could be oncogenic mutations. Until recently, the connection between
intrinsically regulated by genotype and epigenotype, or extrinsically metabolism and epigenetics was emphasized in cancer biology.
affected by tumor microenvironment (TME). Metabolism reprogramming is known to affect epigenetic
Epigenetics was firstly established by Conrad Waddington in landscapes through different mechanisms. Conversely,
1942 (Cairns et al., 2011), which refers to the study of modification epigenetic regulation contributes to altered metabolic
in gene expression or cellular phenotype that occurs without activities. Hence, cancer metabolism and epigenetics are
changes in DNA nucleotide sequences (Possemato et al., 2011). highly interwoven in a reciprocal manner. This great
The basic unit of chromatin organization is nucleosome, which is breakthrough has gained wide interest in targeting both
composed of DNA and histone octamer. Chromatin state is a altered metabolism and modified epigenetics. However,
dynamic event that controls gene transcription. Epigenetic whether these two hallmarks synergistically attack tumor
modification of gene expression occurs at the DNA, histone, remains unknown. Noteworthy, such a complex relationship
and RNA level. The most well-characterized examples are DNA has the potential to affect immune system, such as trained
methylation, histone methylation, acetylation, phosphorylation, immunity, T cell activation, macrophage activation. A novel
ubiquitination, and microRNA-dependent gene silencing strategy is to target epigenetics-metabolism axis in
(Margueron and Reinberg, 2010). It is widely recognized that combination with immunotherapy, potentially boosting more
epigenetic dysfunction is a common feature of many cancers potent antitumor responses.

Chen et al. 10.3389/fphar.2022.935536
TABLE 1 Fundamental interface of metabolism and epigenetics.
Metabolism pathway Metabolic enzyme Metabolites Epigenetic enzyme Epigenetic regulation
One-carbon cycle MAT SAM/SAH KMT, PRMT DNA and histone methylation
TCA cycle FADS FAD/FADH2 LSD Histone demethylation
TCA cycle IDH, GLUD α-KG TET and JmjC demethylase DNA and histone demethylation
TCA cycle ACSS1, ACSS2, ACLY Acetyl-CoA/CoA HAT Histone acetylation
Glycolysis/TCA cycle NMNAT NAD+/NADH SIRT, PARP Histone deacetylation
TCA cycle NA AMP/ATP AMPK Phospharylation
Hexosamine NA GlcNac OGT GlcNacylation
MAT, methionine adenosyltransferase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; KMT, Lysine methyltransferase; PRMT, protein arginine methyltransferase; TCA,
Tricarboxylic acid; ACSS, acetyl-CoA synthetase short-chain family member; ACLY, ATP citrate lyase; HAT, histone acetyltransferase; NMNAT, nicotinamide mononucleotide
adenylytransferase; PARP, poly-ADP ribose polymerase; FADS, flavin adenine dinucleotides; LSD, lysine specific demethylase; IDH, isocitrate dehydrogenase; GLUD, glutamate
dehydrogenase; TET, ten-eleven translocation methylcytosine dioxygenase; JmjC, Jumonji N/C-terminal domains; ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP,
adenosine monophosphate; AMPK, AMP-activated protein kinase; GlcNac, O-linked N-acetylglucosamine; OGT, O-linked N-acetylglucosamine transferase; NA, Not Applicable
In this review article, we firstly summarize the metabolic interface between metabolism and epigenetics has been
alterations that drive epigenetic changes in cancer, and vice versa. summarized in Table 1.
We next describe the therapeutic opportunities by targeting
metabolism-epigenetic crosstalk. Further, we discuss the
principles linking metabolism, epigenetics to immunity and 2.2 SAM/SAH ratio affects DNA and
introduce the rationale for novel immunotherapy-based histone methylation
combinations. Our aim is to introduce the fundamentals of
connection between metabolism and epigenetics in cancer 2.2.1 SAM/SAH
biology and discuss potential pharmacological strategies that DNA and histone methylation are respectively mediated by
can exploit the metabolism and epigenetics in malignancy. DNA methyltransferase (DNMT) enzymes and histone
methyltransferase (HMT) enzymes (Varier and Timmers,
2011), both of which utilize S-Adenosyl-methionine (SAM) as
2 Metabolism shapes the epigenetic a major methyl donor. Methylation is to transfer a methyl group
state of cancer cells from SAM to the receptor, and the remaining residue is
S-adenosyl-homocysteine (SAH) that is inhibitory to
Tumors are likely to harbor epigenetic changes driven by methyltransferase. SAM is derived from one-carbon
their cellular metabolism. There are several different mechanisms metabolism that plays integral roles in DNA synthesis and
explaining the influx from metabolism to chromatin. methylation reaction. The most studied metabolites, like
glucose and glutamine, feed into the one-carbon cycle and
increase the availability of SAM. Both global DNA
2.1 Metabolites are either substrates or co- hypomethylation and site-specific CpG hypermethylation are
factors for epigenetic enzymes frequent epigenetic abnormities observed in cancer (Sandoval
and Esteller, 2012), while histone methylation may activate or
Epigenetic enzymes employ several metabolic intermediates repress gene transcription (Vakoc et al., 2005; Berger, 2007;
as substrates or co-factors to carry out post-translational Bernstein et al., 2007). Therefore, SAM/SAH ratio directly
modifications of DNA and histone (Katada et al., 2012), affect the methylation status of chromatin.
which in turn influence metabolic gene expression. Examples
of such metabolites include: SAM, α-KG, and FAD that
participate in DNA and histone methylation; acetate, acetyl- 2.3 TCA cycle metabolites regulate DNA
CoA and NAD+ that mediate histone acetylation (Thakur and and histone demethylation
Chen, 2019). These key metabolites are produced in multiple
pathways mediated by metabolic enzymes: SAM from one- 2.3.1 TCA cycle metabolites
carbon metabolism, α-KG and FAD+ from the TCA cycle, Reversal of DNA and histone methylation is catalyzed by
acetyl-CoA from glycolysis and glutamine metabolism, and DNA and histone demethylase. Histone demethylation is
NAD+ from the conjunction of glycolysis and oxidative regulated by two classes of enzymes: lysine-specific
phosphorylation (Wang and Lei, 2018). The fundamental demethylase family (LSD1 and LSD2) (Fang et al., 2010) and

Chen et al. 10.3389/fphar.2022.935536
JmjC-containing family, both of which are dependent on ferrous the demand of acetate as a substitute carbon source for lipid
adenine dinucleotide (FAD). Also, JmjC family is ferrous ion- synthesis (Kamphorst et al., 2014). Consequently, acetate must be
dependent oxygenase requiring α-KG for the enzymatic converted to acetyl-CoA either by ACSS1 in mitochondria or by
activation (Shi et al., 2005; Klose et al., 2006). Likewise, DNA ACSS2 in the cytoplasm or nucleus (Figure 1). There is already
demethylation is modulated by TET-family proteins (TET1, evidence that both acetate and acetyl-CoA facilitate tumor
TET2, and TET3), which are also FAD- and α-KG-dependent growth by histone acetylation in yeast (Cai et al., 2011).
dioxygenase (Bhutani et al., 2011; He et al., 2011; Ito et al., 2011). ACSS2, as the only known enzyme utilizing free acetate in
Both FAD and α-KG are intermediary metabolites produced in nucleus (Moffett et al., 2020), could shape the epigenetic
TCA cycle. Other TCA metabolites, such as succinate and landscape via selective histone acetylation. More specifically,
fumarate, are identified as antagonists for JmjC-containing ACSS2 is translocated from cytoplasm to the nucleus
family demethylase (Xiao et al., 2012). Therefore, TCA cycle supplying a local of acetyl-CoA (Chen et al., 2017), which
metabolites regulate epigenetic marks on DNA and histone. contributes to all kinds of acetylation reactions in cell nuclei.
One study indicated (Gao et al., 2016), under hypoxia condition,
ACSS2 catalyzes the conversion of acetate to acetyl-CoA in the
2.4 Acetyl-CoA, NAD+ and acetate hepatoma carcinoma cells, facilitating the hyper-acetylation of
influence histone acetylation histone K3K9, H3K27, and H3K56 and thereby upregulating the
expression of lipogenic enzymes. This explains how acetate links
2.4.1 Acetyl-CoA metabolite levels to epigenetic regulation and gene transcription.
Histone acetylation is another important epigenetic Otherwise, ACSS2 acts to recycle acetate generated from HDAC-
modification that depends on histone acetyltransferase (HAT) mediated deacetylation reactions under metabolic stresses,
and histone deacetylase (HDAC) (Shahbazian and Grunstein, replenishing the cytoplasmic and nuclear storage and thus
2007). Acetyl-CoA is a pivotal metabolite for energy production supporting chromatin remodeling events (Moffett et al., 2020).
and anabolic process (Wellen and Thompson, 2012; Pietrocola
et al., 2015). HAT transfers the acetyl moiety of acetyl-CoA to
lysine residues of histone, while HDAC is responsible for 2.5 ATP/AMP ratio controls histone
removing the acetyl group to reverse histone acetylation. It is phosphorylation
well-known histone acetylation can increase nucleosome
mobility and activate transcription elongation (Racey and 2.5.1 ATP/AMP
Byvoet, 1971; Cai et al., 2011). Previous study figured out, in Some kinase could be translocated to nucleus and straightly
yeast and mammalian cells, the glycolysis dynamically governs phosphorylate histone (Baek, 2011). For example, AMP-
the acetyl-CoA quantity and correspondingly regulates HAT- activated protein kinase (AMPK) acts as sensory signal of
dependent histone acetylation (Friis et al., 2009; Cai et al., 2011; ATP/AMP ratio (Hardie, 2011). Conversion of ATP to AMP
Lee et al., 2014). aids in anabolic process via AMPK-mediated pathway, whereas
catabolism relies on the opposite switch from AMP to ATP.
2.4.2 NAD+ Owing to metabolic stress and low ATP/AMP ratio, AMPK is
Histone deacetylation is catalyzed by two kinds of activated to phosphorylate histone H2B on serine 36 that triggers
deacetylases: zinc-dependent and NAD+-dependent proteins. gene expression in favor of tumor survival (Bungard et al., 2010).
Deacetylation results in the tight wrapping of DNA by histone
and hence promotes gene repression and silence (Imai et al.,
2000; Finkel et al., 2009). Similarly, some metabolites function as 2.6 Hexosamine biosynthetic pathway
antagonists that inhibit the activities of HDAC. For example, mediates protein glycosylation
butyrate can robustly antagonize HDACs I, II and IV (Candido
et al., 1978). Also, NAD+ is regarded as a catalytic co-factor for 2.6.1 O-GlcNAc
HDAC III to mediate histone deacetylation (Thakur and Chen, Protein glycosylation is carried by opposite actions of
2019). Further, evidence illustrated higher histone deacetylation O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA),
levels are associated with poorer prognosis (Kurdistani, 2011). respectively responsible for the addition and removal of
O-GlcNAc from proteins. One of the most common features
2.4.3 Acetate that cancer cells demonstrate is OGT overexpression leading to
Acetate has been implicated in driving histone acetylation protein hyper-glycosylation (Pinho and Reis, 2015). Typically,
and deacetylation. Recently, the role of acetate in the interaction O-GlcNAc is produced in Hexosamine biosynthetic pathway
between metabolism and epigenetics has been emphasized (HBP). In this pathway, glucose is firstly converted into glucose-
during tumorigenesis. Under hypoxia, cancer cells decrease 6-P and then fructose-6-P. A series of metabolites, such as acetyl-
the reliance on glucose and glutamate and inversely increase CoA, UTP, glutamine, subsequently participate in the production

Chen et al. 10.3389/fphar.2022.935536
TABLE 2 Metabolites are either substrates or co-factors for epigenetic enzymes in cancer biology.
Epigenetic Examples Substrates or Co-factors Mechanisms

enzymes
DNA methylation and demethylation
DNA DNMTs SAM/SAH (methionine cycle) Methyl donors for methyltransferases

methyltransferase
DNA demethylase TETs α-KG, 2HG, succinate, fumarate, vitamin C, Co-factors for α-KG-utilizing dioxygenases; Inhibition of α-KG-
FAD/FADH2 utilizing dioxygenases
Histone acetylation and deacetylation
Histone HATs Acetyl-CoA (TCA cycle/acetate) Acetyl donors for acetyltransferases

acetyltransferase
Histone deacetylases HDAC, SIRT NAD+, nicotinamide, β-Hydroxybutyrate, Activation or inhibition of histone deacetylase; Histone succinylation
succinyl-CoA, butyrate
Histone methylation and demethylation
Histone Lysine: PKMTs, SAM/SAH (methionine cycle) Methyl donors for methyltransferases
methyltransferase Arginine: PRMTs
Histone KDMs: LSD, JmjC α-KG, 2HG, succinate, fumarate, vitamin C, Co-factors for α-KG-utilizing dioxygenases; Positive regulators of LSD;
demethylases FADH2 Inhibition of α-KG-utilizing dioxygenases
Histone phosphorylation
Histone kinase AMPK ATP/AMP Phosphate donors for protein kinase
Protein glycosylation
Protein glycosylase OGT, OGA O-GlcNAc O-GlcNAc donors for protein glycosylation
of UDP-GlcNAc, the activated substrate for O-GlcNAcylation. fluctuating concentrations could regulate the epigenetic profile
Therefore, HBP integrated various metabolism pathways. and affect gene transcription.
Upregulation of HBP is associated with abnormal
O-GlcNAcylation and more invasive behavior (Caldwell et al.,
2010; Wellen et al., 2010; Itkonen et al., 2013; Onodera et al., 2.7 Genetic mutations of metabolic
2014; Lucena et al., 2016). Recently, studies confirm that enzyme that modify epigenome
enhanced glycolysis aids in protein glycosylation (Wong et al.,
2017). Moreover, OGT is associated with TETs to control Mutations in metabolic enzymes subject the cells to
O-GlcNAcylation of histone H2B for activation of gene tumorigenesis. Such changes facilitate the accumulation of
transcription (Chen et al., 2013; Ito et al., 2014), while OGT is metabolites that ultimately lead to epigenetic dysfunction
coordinated with EZH2 to modulate H3K27me3 for silence of (DeBerardinis and Chandel, 2016) and immunosuppression
tumor suppressor genes (Chu et al., 2014). (Table 3).
Taken together, either methylation or acetylation controls One example is to generate oncometabolite. Oncometabolite
the activation and repression of gene transcription. This event is refers to metabolites whose great quantity increases markedly in
balanced by various epigenetic enzymes. The cellular metabolites, tumors compared with normal cells (Nowicki and Gottlieb,
such as SAM/SAH, acetyl-CoA/CoA, NAD+/NADH, ATP/AMP 2015). This new term is used to describe metabolites for
ratio, commonly act as substrate or co-factors for these which 1) there is a well-characterized mechanism connecting
epigenetic-based enzymes (Table 2, Figure 2). Their mutations in metabolic enzymes to accumulation of a certain

Chen et al. 10.3389/fphar.2022.935536
FIGURE 2
Cellular metabolites serve as co-factors or substrates for epigenetic enzymes. Addition or removal of epigenetic marks is catalyzed by
epigenetic enzymes, of which process relies on several critical metabolites. SAH/SAM, NAD+/NADH, Acetyl-CoA/Co-A, ATP/ADP ratio act as
important molecules or signals governing epigenetic modifications. In addition, Metabolites such as succinate, fumarate, 2-HG, and lactate could
inhibit the activity of epigenetic enzymes. HMT, histone methyltransferase; LSD, lysine-specific histone demethylase; JHDM, Jumonji domain-
containing histone demethylase; HAT, histone acetyltransferase; HDAC, histone deacetylase; SIRT, sirtuins; DNMT, DNA methyltransferase; TET, ten-
eleven translocation methylcytosine dioxygenase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; α− KG, α-ketoglutarate; NAM,
nicotinamide; NAD+, nicotinamide adenine dinucleotide (oxidized); FAD, flavin adenine dinucleotide (oxidized); FADH2, flavin adenine dinucleotide
(reduced); FH, fumarate hydratase; SDH, succinate dehydrogenase; IDH1/2, isocitrate dehydrogenase 1/2; EZH2, enhancer of zeste 2 polycomb
repressive complex 2 subunit; KMT2D, histone-lysine N-methyltransferase 2D. AMPK, AMP-activated protein kinase; Pi, phosphate group; OGT,
O-GlcNAc transferase; OGA, O-GlcNAcase.
metabolite; 2) there is convincing evidence for some metabolites DNA and histone (Figueroa et al., 2010; Losman et al., 2013).
as a predisposition to tumorigenesis. Oncometabolites are Mutant-IDH1/IDH2 and their relationship to D2HG have been
frequently associated with aberrant DNA damage and enable reviewed extensively elsewhere (Losman and Kaelin, 2013).
the tumor microenvironment (TME) more invasive. Currently, These mutations frequently occur in gliomas, blood cancer,
D-2-hydroxyglutarate (D2HG), L-2-hydroxyglutarate (L2HG), glioblastoma multiforme, and cholangiocarcinoma (Yan et al.,
succinate, fumarate, and lactate are recognized oncometabolites. 2009; Vatrinet et al., 2017). Another reduced form of
α-ketoglutarate is L2HG that is accumulated due to loss-of-
2.7.1 D2HG and L2HG function mutations of L-2-hydroxyglutarate dehydrogenase
The first emphasized oncometabolite is D2HG, a reduced (L2HGDH) (Aghili et al., 2009; Rogers et al., 2010). The
form of the TCA cycle intermediate α-ketoglutarate, which is increased levels of L2HG have been observed in renal cell
scarce in normal tissues but rises to a higher concentration in carcinoma and brain tumors (Shim et al., 2014).
tumors (Xu et al., 2011). This oncometabolite is caused by
NADP+-dependent isocitrate dehydrogenase (IDH1 or IDH2) 2.7.2 Succinate and fumarate
mutation. High levels of D2HG inhibit the activity of TET-family This principle also applies to another two oncometabolites:
DNA and JmjC family histone demethylase. Overall, cancer cells succinate and fumarate (Yang et al., 2013). Mutational inactivation
harboring IDH1/IDH2 mutations display hypermethylation of of succinate dehydrase (SDH) and fumarate hydratase (FH)

Chen et al. 10.3389/fphar.2022.935536
TABLE 3 The effect of oncometabolites on epigenetic dysfunction and immunosuppression.
Oncometabolite Metabolic Epigenetic Immunosuppressive Malignancies References

enzymes dysfunction effect
D-2- IDH1/2 DNA and histone NA Glioblastoma multiforme, Dang et al. (2009); Amary et al.
hydroxyglutarate hypermethylation ALL, Chondrosarcoma, (2011); Borger et al. (2014); Shim
Cholangiocarcinoma et al. (2014); Waterfall et al. (2014);
Colvin et al. (2016)
L-2-hydroxyglutarate L2HGDH DNA and histone NA Brain tumors, Renal cell Aghili et al. (2009); Rogers et al.
hypermethylation carcinoma (2010)
Succinate SDH DNA and histone TAM marker gene expression ↑ Pheochromocytomas, Hao et al. (2009); Bardella et al.
hypermethylation Paragangliomas (2011); Zhang et al. (2011); Yang
IL-6 secretion ↑
et al. (2013); Williamson et al.
(2015); Jiang and Yan, (2017); Mu
et al. (2017)
Fumarate FH DNA and histone Neutrophils, T-cell, B-cell Pheochromocytomas, Kinch et al. (2011); Fieuw et al.
hypermethylation response ↓ Paragangliomas (2012); Sullivan et al. (2013); Zheng
Inhibiting DC maturation et al. (2013b); Castro-Vega et al.
(2014); Shanmugasundaram et al.
CD150, CD40, CD86 expression ↓ (2014); Yang et al. (2014); Jin et al.
CTLA-4, PD-L1 expression ↑ (2015); Zheng et al. (2015)
IL-6, IL-1β, TNF-α secretion ↓
Lactate MCT/LDH Histone acetylation PD-1, PD-L1, CTLA-4 Lung carcinoma, Melanoma, (Colegio et al., 2014; El-Kenawi
expression ↑ Prostate cancer et al., 2019)
Inhibiting the differentiation of
monocytes to DCs
Inhibiting the differentiation of
progenitor cells to CD4+ and CD8+
T-cell
IDH1/2, isocitrate dehydrogenase; L2HGDH, L-2-hydroxyglutarate dehydrogenase; SDH, succinate dehydrogenase; FH, fumarate hydratase; MCT, monocarboxylate transporter; LDH,
lactate dehydrogenase; TAM, tumor-associated macrophages; ALL, acute lymphoblastic leukemia; NA, not applicable.
respectively contributes to the stacking up of succinate and fumarate could downregulate neutrophils, T-cell, and B-cell
fumarate (Baysal et al., 2000; Tomlinson et al., 2002; Gottlieb responses, inhibit dendritic cell (DC) maturation, and motivate
and Tomlinson, 2005), both of which interfere with α KG- CTLA-4 and PD-L1 expression.
dependent dioxygenases, namely DNA and histone demethylase
(Nowicki and Gottlieb, 2015). Consequently, deficiency of SDH 2.7.3 Lactate
and FH activity results in DNA and histone hypermethylation, To ensure adequate ATP supply, the malignant
supporting the notion that oncometabolites are potent modifiers of transformation is associated with an upregulated glycolysis (de
the epigenome. Other studies provided additional layers of Groof et al., 2009). Cancer cells upregulate glycolytic enzymes
metabolic control of epigenome. FH is observed to be and metabolic transporters, which is connected with lactate
O-GlycNAcylated and consequently bring changes in histone overproduction. A new discovery considered lactate might
methylation (Wang et al., 2017). Another research proposed have an effect on lysine residues of histone, acting in a similar
that the enrichment of fumarate facilitates epithelial-to- way to acetylation and gene activation (Hou et al., 2019; Zhang
mesenchymal-transition (EMT) through inhibiting TET et al., 2019). This phenomenon is based on the conversion of
methylase (Sciacovelli et al., 2016). Therefore, oncometabolites lactate to acetyl residues and thereby stimulates tumor
perform their biological functions outside of conventional angiogenesis. The accumulation of lactate also exerts an
pathways and play quantitative roles leading to aberrant immunosuppressive effect on TME through inhibiting the
epigenome. Additionally, emerging evidence supports that both differentiation and maturation of DC and T cell (Gottfried
succinate and fumarate contribute to immunosuppressive et al., 2006).
polarization and T cell exhaustion, thereby making the tumor
microenvironment more suitable for cell migration. Explicitly, 2.7.4 PHGDH, PRODH, and NNMT
succinate can upregulate tumor-associated macrophages (TAM) Cancer-specific mutations of metabolic enzymes with
marker gene expression, such as Arg1, Fizz1, Mhl1, and Mgl2. The implications in epigenetic regulation have been reported.
expression of succinate receptor 1 is also associated with immune Phosphoglycerate dehydrogenase (PHGDH) is overexpressed
inhibitory proteins, such as PD-L1, PD-1, and CTLA-4. Moreover, in breast cancer and melanoma (Locasale et al., 2011;

Chen et al. 10.3389/fphar.2022.935536
Possemato et al., 2011), directing the metabolism toward the gluconeogenesis. DNA methylation contributes to a higher
serine biosynthesis pathway. Serine provides methyl donors to glycolytic influx, which is beneficial to the proliferation of
one-carbon metabolism, thereby affecting cellular epigenetics tumor cells.
(Locasale, 2013). Conversely, PHGDH silence can
downregulate serine synthesis leading to tumor growth
suppression (Locasale et al., 2011; Possemato et al., 2011). 3.2 Histone modifications
Another example is proline dehydrogenase (PRODH) that
catalyzes proline to produce pyrroline-5-carbonxylate (P5C), Sirtuins (SIRTs), an enzyme catalyzing histone deacetylation,
which is sequentially converted into glutamate and α-KG to has been shown to function in cancer metabolism. Examples of
affect epigenome (Phang et al., 2013). Studies showed epigenetic enzymes are SIRT6, SIRT7, and SIRT2.
amplification of PRODH in immunodeficient mice displayed
tumor-suppressive characters (Liu et al., 2010). Nicotinamide 3.2.1 SIRT6
N-methyltransferase (NNMT) also modulates epigenetic events NAD+-dependent SIRT6 optimizes energy homeostasis by
in cancer cells. NNMT catalyzes the transfer of methyl group regulating histone acetylation (Xiao et al., 2010). SIRT6 could
from SAM to nicotinamide. Overexpression of NNMT hampers directly repress glycolysis in the HIF1 α-dependent way, thereby
SAM-dependent methylation of DNA and histone, along with it acts as a tumor suppressor by inhibiting the Warburg effect
the procurement of more invasive phenotype (Ulanovskaya et al., (Zhong et al., 2010; Sebastián et al., 2012). Instead,
2013). SIRT6 knockdown shifts the cell metabolism towards a
As summarized, mutations in genes encoding metabolic “glycolytic phenotype” inducing malignancy aggressiveness.
enzymes have been recognized in caner, but they are rare. Specific deletions in SIRT6 have been observed in colon,
These lesions in genes related to metabolism constitute a new pancreatic, and hepatocellular cells (Zhang and Qin, 2014).
class of cancer-associated mutations that is able to subvert Also, a growing body of evidence demonstrates that
normal epigenetic regulation. It is tempting to speculate SIRT6 upregulates hepatic gluconeogenic gene expression and
that these mutations provide the hope of identifying novel increases glycerol release from adipose tissue. These findings
targets. underline the potential to target SIRT6 for modulating cancer
metabolism (Roichman et al., 2021).
3 Epigenetic events contribute to 3.2.2 SIRT7

altered metabolism in cancer SIRT7 could directly interacts with MYC that mediates the
transcription of almost all the genes involved in glycolysis and
3.1 DNA methylation glutaminolysis (Barber et al., 2012; Shin et al., 2013).
SIRT7 selectively catalyzes H3K18 deacetylation that is a
A number of metabolic enzymes are altered attributing to repressive mark (Wong et al., 2017). Hence, SIRT7 plays an
DNA methylation. Examples of such enzymes involve Fructose- opposite role in MYC-mediated metabolic reprogramming.
1,6-bisphosphastase (FBP-1), fructose-1,6-bisphosphatase (FBP-
2), glucose transporter 1 (GLUT-1), Hexokinase (HK2), and 3.2.3 SIRT2
pyruvate kinase isozyme 2 (PKM-2). Compared to SIRT6/7, SIRT2 promotes cancer metabolism
As reported, promoter hypermethylation leads to the silence through stabilizing MYC (Liu et al., 2013). SIRT2 specifically
of FBP-1 and FBP-2 in gastric, colon, liver, and breast cancers deacetylases H4K16, resulting in decreased expression of
(Kamphorst et al., 2014; Gao et al., 2016). Both FBP-1 and FBP-2 ubiquitin-protein ligase NEDD4. NEDD4 serves as a negative
are rate-limiting enzymes for gluconeogenesis that antagonize regulator of MYC through ubiquitination and degradation
glycolysis. Theoretically, the silence of FBP-1 or FBP-2 (Wong et al., 2017). Consequently, SIRT2 facilitates MYC-
contributes to glycolytic phenotype, supporting dependent transcription and oncogenesis.
macromolecular biosynthesis and energy production. DNA
methylation also mediates the gene overexpression of GLUT-1
that transports glucose from tumor microenvironment to 4 Novel cancer therapy targeting
cytoplasm (Lopez-Serra et al., 2014). Oppositely, promoter metabolism-epigenetic crosstalk
hypomethylation results in the upregulation of HK2 in
glioblastoma and hepatic carcinoma (Chen et al., 2011; Wolf 4.1 Novel targets for cancer metabolism
et al., 2011) and the overexpression of PKM2 in multiple cancer
types (Desai et al., 2014). Targeting metabolic enzymes might be novel strategy for
In brief, increased HK2 and PKM-2 levels promote enhanced cancer therapy. LDH-A, a metabolic enzyme responsible for
glycolysis, while the silence of FBP-1 and FBP-2 limit the conversion of pyruvate to lactate, was recognized as the

Chen et al. 10.3389/fphar.2022.935536
first metabolic target of the oncogene MYC (Shim et al., 1997). promise for cancer therapy. In models of hepatocellular
Appealing evidence manifested genetic or pharmacologic carcinoma, genetic loss of ACSS2 is likely to reduce
ablation of LDH-A is able to dwindle MYC-driven tumors tumor burden (Comerford et al., 2014). Human
in the xenograft models (Fantin et al., 2006; Le et al., 2010). glioblastoma is sensitive to inhibitors of ACSS2 as well
Inhibition of LDH-A could delay the progression of myeloid (Mashimo et al., 2014).
leukemia (Wang et al., 2014) and diminish NSCLC without
systemic toxicity in genetically engineered mouse models (Xie
et al., 2014). Hence, LDH-A is a promising target in MYC- 4.2 Reversal of epigenetic dysfunction by
mutant tumors. Another attractive target is the glycolytic targeting metabolism
protein Hexokinase (HK2). Many tumors express high
levels of HK2. Specific inhibition of HK2 delays tumor Over the past decades, a few studies represent how advances
progression in mouse models of NSCLC and breast cancer of metabolic effects on epigenetics can be translated into
(Patra et al., 2013). Targeting HK2 might be efficacious in potential therapies. One strategy is to reverse epigenetic
highly glycolytic tumors. Besides, PHGDH, an enzyme that dysfunction by targeting cancer metabolism (Table 4).
functions in the de novo serine synthesis, is found to Glycolysis inhibitors could reverse global histone
overexpress in human melanoma and breast cancers hyperacetylation. 2-Deoxyglucose (2-DG), a glucose
(Locasale et al., 2011; Possemato et al., 2011). Targeting analog, is a rate-limiting enzyme for glycolysis. The use of
PHGDH in the one-carbon metabolism has been shown to 2-DG inhibits acetyl-CoA levels, which rationally promotes
delay tumor progression, though more studies are needed to histone deacetylation in multiple cancer cell lines. Hence,
confirm it. Additionally, the concept of oncometabolite glycolysis inhibition represents a candidate target for
opened a new window for targeted therapy. Small regulating histone acetylation. Glutaminolysis produces α−
molecules targeting IDH1/IDH2 demonstrate positive KG and acetyl-CoA. Glutaminase (GLS) is an extensively
outcomes in ongoing clinical trials (Yen et al., 2017). Taken investigated target. Relevant inhibitors include CB-839,
together, targeting metabolic enzyme holds great promise in compound 968, and BPTEs. For example, compound-968
the treatment of malignancy (Olivares et al., 2015). suppresses histone H3K4me3 in breast cancer and Zaprinast
Targeting metabolism pathways, such as glycolysis, decreases H3K9Me3 in IDH-mutant cancer cells. The utility
glutamine metabolism, mitochondrial metabolism, and of GLS inhibitors could restore epigenetic dysfunction,
autophagy, provides new opportunities for drug discovery particularly in IDH 1/2-mutant tumors. In addition, IDH
scheme. In the certain context, metabolites produced from 1/2 inhibitors specifically reduce the production of 2-HG
these metabolic pathways are able to affect epigenome. For that is an oncometabolite in IDH 1/2-mutant cells. For
example, metformin, an anti-diabetic drug, has been instance, AG-221 and AGI-6780 treatment result in
spotlighted on mitochondrial-mediated metabolic activity demethylation status of DNA and histone in IDH 2-
emerging as a key target for cancer therapy (Weinberg and mutant tumors; AGI-5198 prompts demethylation of
Chandel, 2015). Because diabetic patients treated with H3K9me3 and H3K27me3 in chondrosarcoma cells; GSK-
metformin not only control their blood glucose level but 321 causes DNA hypomethylation in AML cells. NNMT
also improve survival rate if cancer was diagnosed already inhibitors lead to reduced SAM levels, which in turn
(Evans et al., 2005). Biguanide phenformin also displayed downregulate histone methylation. The summarized
anti-tumor effect by inhibiting mitochondrial complex I concepts are illustrated in Table 4.
(Birsoy et al., 2014). Another example is BPTES [bis-2-(5-
phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide], one
inhibitor of glutaminase activity, is being explored for anti- 4.3 Reversal of metabolism rewiring by
cancer characteristics (Xiang et al., 2015). Autography offers targeting epigenetics
amino acids that fuel TCA cycle. Autography inhibition is
confirmed to decrease tumor progression without significant Instead, using epigenetic drugs could modulate metabolism
toxicity in the mouse models of NSCLC and pancreatic rewiring as well (Table 5).
cancers (Son et al., 2013; Karsli-Uzunbas et al., 2014). An There are two kinds of DNMT inhibitors therapeutically
alternative approach is to target acetate metabolism. As targeting DNA methylation, respectively named 5-azacytidine
discussed above, mitochondria conventionally provide and 5-aza-2′-deoxycytidine. Both of them have been approved by
acetyl-CoA to the normal cells, whereas cancer cells also FDA to treat myelodysplastic syndrome (MDS). IDH 1/2-mutant
utilize acetate to support cell survival under hypoxia or tumors carrying DNA hypermethylation show a high sensitivity
nutrient deprivation (Schug et al., 2015). ACCS2, a to DNMT inhibitor. In IDH 1-mutant glioma models, both of 5-
cytosolic enzyme that converts acetate to acetyl-CoA, is azacytidine and 5-aza-2′-deoxycytidine induced tumor
dispensable for acetate metabolism and holds great regression. When inducing the differentiation of IDH-mutant

Chen et al. 10.3389/fphar.2022.935536
TABLE 4 Reversal of epigenetic dysfunction by targeting metabolism.
Target Metabolic Pharmacological Mechanism Indications References

pathway enzyme agents
Glycolysis Hexokinases 2-DG (phase-I/II) 2-DG suppresses hexokinase that lung cancer, breast Chen and Guéron, (1992); Liu
is a rate-limiting enzyme for cancer, pancreatic et al. (2015)
glycolysis; 2-DG reduces acetyl- cancer, prostate cancer,
CoA level, which inhibits the lymphoma
acetylation of histones in various
cancer cell lines
Glutaminolysis Glutaminase (GLS) CB-839 (phase-I); GLS inhibitors reduce acetyl- AML, ALL, MM, NHL, Robinson et al. (2007); Wang
Compound-968; Zaprinast CoA and 2-HG level; pancreatic carcinoma et al. (2010a); Simpson et al.
Compound-968 decreases (2012a); Simpson et al.
histone H3K4me3 in breast (2012b); Elhammali et al.
cancer and Zaprinast reduces (2014)
H3K9me3 in IDH1-mutant
cancer cells
Serine/glycine PHGDH shRNA to PHGDH Inhibiting the process of de novo NA Locasale et al. (2011);
metabolism serine synthesis Possemato et al. (2011)
One-carbon SAH hydrolase DZNep; Adenosine Both agents could increase the NA Jiang et al. (2008); Miranda
cycle Dialdehyde SAH/SAM ratio and decrease et al. (2009); Momparler et al.
DNA and histone methylation (2012); Schäfer and
Balleyguier, (2013);
Momparler and Côté, (2015)
IDH1 inhibitor IDH1-mutant AG-120, IDH305, AG-881, IDH1 inhibitors suppress the AML, solid tumors, Rohle et al. (2013); Zheng et al.
BAY1436032, FT-2102, AGI- production of 2-HG that is a kind gliomas, hematologic (2013a); Davis et al. (2014);
5198, GSK-321 of oncometabolite in IDH1- malignancies Deng et al. (2015); Kim et al.
mutant cells; AGI-5198 prompts (2015); Li et al. (2015);
demethylation of H3K9me3 and Okoye-Okafor et al. (2015)
H3K27me3 in IDH1-mutant
chondrosarcoma cells; GSK-321
induces DNA hypomethylation
in IDH1-mutant AML cells
IDH2 inhibitor IDH2-mutant AG-221, AG-881, AGI-6780 IDH2 inhibitors suppress the AML, solid tumors, Wang et al. (2013); Kernytsky
production of 2-HG that is a kind gliomas, hematologic et al. (2015)
of oncometabolite in IDH2- malignancies
mutant cells; AG-221 and AGI-
6780 prompt demethylation of
DNA and histone in IDH2-
mutant cancer cells
NNMT inhibitor N-Methylnicotinamide Nicotinamide NNMT inhibitors reduce SAM NA Kraus et al. (2014)
N-methyltransferase level and histone methylation in
(NNMT) NNMT-overexpressed cells
2-DG, 2-Deoxyglucose; GLS, glutaminase; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; MM, multiple myeloma; NHL, Non-Hodgkin Lymphoma; NA, not applicable.
glioma cells, 5-aza-2′-deoxycytidine displayed a more potent 4.4 Combination therapy of metabolism
efficacy than IDH inhibitors. Therefore, targeting epigenetics and epigenetics
is a complementary approach to modulate the effect of
oncometabolites in tumor. HDAC inhibitors could induce Advancements in the area of cancer drug discovery have
histone acetylation and reverse gene silence caused by spotlighted on the inhibitors of metabolic pathways and cancer
HDACs. Growing evidence suggests HDAC inhibitors epigenetics. However, the efficacy of epigenetic inhibitors alone is
significantly suppressed glycolysis in various cancer types, not satisfactory, and this approach is usually prone to drug
such as lung cancer, breast cancer, and multiple myeloma. resistance (Zhang et al., 2020). Also, cancer cell could be
These findings manifest that inhibition of HDAC might drug-resistant to suppression of a particular metabolic
reverse glycolytic phenotype. The modulation of SIRT pathway by upregulating compensatory pathways or
activator and inhibitor holds promise as their regulatory roles expressing alternative isoforms. Further, inhibitions of
in metabolism reprogramming. MiRNA-based therapeutics, such metabolic enzymes might produce systemic toxicity owing to
as miRNA-143, also inhibit glycolysis by targeting hexokinase-II their physiological role in normal cells (Pearce et al., 2013; Ito and
3′-UTR. More examples are summarized in Table 5. Suda, 2014; Erez and DeBerardinis, 2015). To achieve the

Chen et al. 10.3389/fphar.2022.935536
TABLE 5 Reversal of metabolism reprogramming by targeting epigenetics.
Inhibitors Target enzyme Pharmacological Mechanism Indication References

agents
DNMT inhibitor DNA Azacitidine (approved) Non-selective inactivating DNMT1, MDS, AML Borodovsky et al. (2013); Turcan
methyltransferases DNMT3A, and DNMT3B; Reversing the et al. (2013)
Decitabine (approved)
hypermethylation status in IDH1-mutant
Guadecitabine glioma cells
(phase-III)
KDM inhibitor LSD1 (Lysine ORY-1001 (phase-I) Inhibiting histone demethylation AML, NCT02913443
demethylase) GSK2879552 (phase-I) SCLC, MDS NCT02177812
NCT02034123
HDAC inhibitor Histone deacetylases Romidepsin (approved) Prompting histone acetylation; Reducing T-cell Wardell et al. (2009);
glucose uptake, glycolytic flux, and lactate Lymphoma, Alcarraz-Vizán et al. (2010);
Vorinostat (approved)
metabolism MM Amoêdo et al. (2011); Rodrigues
Panobinstat (approved) et al. (2015)
Belinostat (approved)
SIRT activator SIRT6 (Histone Linoleic acid Activating or inhibiting histone Unknown Feldman et al. (2013)
and inhibitor deacetylases) deacetylation; Free fatty acid activates
Myristic acid
SIRT6 that inhibits glycolysis
Oleic acid
miRNA miRNAs miRNA mimics miRNA reversed silenced miRNA function; Unknown Meng et al. (2007); Gregersen et al.
modulator miRNA-143 could inhibit glycolysis by (2012)
miRNA sponges
targeting hexokinase-II 3′-UTR; Anti-
antisense miRNA-21 could restore PTEN expression
oligonucleotides
DNMT, DNA, methyltransferase; KDM, lysine demethylase; HDAC, histone deacetylase; SIRT, sirtuin; miRNA, microRNA; MDS, myelodysplastic syndrome; AML, acute myeloid
leukemia; SCLC, small cell lung cancer; MM, multiple myeloma; 3′-UTR, 3′-untranslated region.
purpose of less toxicity and potent efficiency, a rational strategy is block H3K27 methylation and consequently activate the
to develop multiple drug combinations. transcription of pro-differentiation genes. Also, metabolic
As an epigenetic regulator, enhancer of zeste homology pathway is likely to downregulate EZH2 activity and thereby
(EZH2) inhibits gene transcription by trimethylation of acts synergistically with EZH2 inhibitors (Zhang et al., 2020).
histone H3K27 in cancer cells. Mounting evidence has More specifically, AMPK is activated in response to energy stress
suggested that EZH2 participated in the alteration of (glucose deficiency) and phosphorylates EZH2 (Cha et al., 2005).
metabolic profiles in cancer through diverse pathways, AKT-mediated phosphorylation of EZH2 suppresses
covering glucose, lipid, amino acid metabolism. Meanwhile, trimethylation of lysine 27 in histone H3, facilitating the
metabolic activities also affect the stability and transcription of target genes to suppress tumor growth (Cha
methyltransferase activity of EZH2, as some metabolites offer et al., 2005; Priebe et al., 2011; Gao et al., 2014; Kim and Yeom,
the donors for EZH2 post-translational modifications (Zhang 2018). Therefore, a combination of EZH2 inhibitors with
et al., 2020). As a promising target, EZH2 inhibitors have been metabolic regulators is a novel strategy to rescue the poor
investigated in preclinical trials, but the effectiveness of effectiveness of EZH2 inhibitor alone (Zhang et al., 2020).
EZH2 inhibitors alone is not satisfactory (De Raedt et al., Briefly, epigenetic and metabolic alterations mediated by
2011; Baude et al., 2014; Huang X. et al., 2018). Recently, EZH2 are highly interlaced, demonstrating a synergistic effect
researchers have found EZH2 inhibitor is able to weaken drug in treating malignancy.
resistance caused by metabolic activities in tumor. Solid tumor is A model whereby linked metabolic-epigenetic programs
subject to hypoxia and glutamine deficiency because of the reflects a new idea to target such an integrated axis. A study
underdeveloped vascular system. Hypoxia induces a metabolic (McDonald et al., 2017) on the evolution of pancreatic ductal
switch from oxidative to glycolytic metabolism, promoting the adenocarcinoma (PDAC) introduced an epigenetic mechanism
dedifferentiation of tumor cells and inducing resistance to radio- that links glucose metabolism to distant metastasis. Remarkably,
and chemotherapy. However, EZH2 inhibitors could directly oxidative branch of the Pentose Phosphate Pathway (ox-PPP)

Chen et al. 10.3389/fphar.2022.935536
TABLE 6 Ongoing clinical trials of combined anti-epigenetic drugs and anti-metabolism drugs.
Identifier Start year Combination therapy Conditions Phase Enrollment
Anti-epigenetics Anti-metabolism drug

drug
NCT02719574 2016 Azacitidine FT-2102 AML/MDS I/II 336

NCT02677922 2016 Azacitidine AG-120 AML I/II 131
NCT03173248 2017 Azacitidine AG-120 AML III 148
NCT03471260 2018 Azacitidine AG-120 Hematologic malignancies I/II 30
NCT03683433 2018 Azacitidine AG-221 AML II 50
NCT03684811 2018 Azacitidine FT-2102 Solid tumors and gliomas I/II 200
NCT04774393 2021 Decitabine AG-120/AG-221 AML I/II 84
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; DNMT, inhibitors: Azacitidine; Decitabine. IDH, inhibitors: AG-120 (Ivosidenib); AG-221 (Enasidenib); FT-2102.
was a driving force for epigenetic programming (histone However, “Trained immunity” is a relatively new term that refers
H3K9 and DNA methylation) that enhanced tumorigenic to myeloid cells from the innate immune system also display
fitness during the distant metastasis. Hence, targeting ox-PPP memory capacity after pathogen exposure (Dominguez-Andres
to reverse malignant epigenetic programs could be effective in and Netea, 2019; Netea et al., 2020b; O’Neill and Netea, 2020).
metastatic PDAC. Another best-studied example is the use of After the first stimuli, innate immune cells, such as macrophage and
AMPK activator metformin, which decreased EZHIP protein monocyte, are epigenetically programmed (Fanucchi et al., 2021).
concentrations, elevated H3K27me3, inhibited TCA cycle, and These epigenetic modifications unfold chromatin and expose
suppressed tumor growth. Consequently, targeting integrated promoter and enhancer regions controlling immune-associated
epigenetic-metabolic pathway shows hopeful therapeutic genes, enabling them accessible to transcription factors (Klemm
efficacy in mice models transplanted with PFA ependymomas et al., 2019) and permitting cells to maintain a “trained” state after
(Panwalkar et al., 2021). rechallenge (Saeed et al., 2014). Specifically, H3K4me3 frequently
Oncogenic signal pathways also play important roles in novel occurs on gene promoters; H3K4me1 and H3K27Ac accumulates
combination therapy. A distinct work on melanoma demonstrated on enhancers (Quintin et al., 2012; Novakovic et al., 2016). As such,
that reduced α-KG levels result in histone hypermethylation and upon the secondary stimulus, immune genes are more robustly
develop the resistance to BRAF inhibitors. The combination of histone transcribed (Fanucchi et al., 2021).
methyltransferase and BRAF inhibitors was sufficient to overcome In addition, some metabolites act as substrates or co-
resistance (Pan et al., 2016). Also, liver kinase B1 (LKB1)-deficiency factors for epigenetic enzymes, which alter chromatin state
tumors carrying KRAS activation would accompany with SAM to cause transcriptional changes that are causal to trained
production, leading to more potent methyltransferase activity and immunity (Fanucchi et al., 2021). For example, acetyl-CoA
increased DNA methylation levels (Kottakis et al., 2016). Combined mediates histone acetylation following immune stimuli
inhibition of DNA methyltransferase and serine metabolism could (Wellen et al., 2009; Christ and Latz, 2019), while SAM
attack LKB-loss tumors with KRAS-positive more aggressively. level regulates DNA and histone methylation to control
Taken together, our understanding in targeting both altered trained immunity (Mentch et al., 2015; Ji et al., 2019). On
metabolism and epigenetics remains at a very early stage. the contrary, NAD + assist histone deacetylation to block
Whether these two hallmarks exert synergistic functions in trained immunity (Yeung et al., 2004; Zhong et al., 2010;
tumor is less explored, though there are a few well-elaborated Lo Sasso et al., 2014; Jia et al., 2018). α-KG-derived
agents in ongoing clinical trials (Table 6). metabolites reduce histone demethylation by competing
with α-KG-dependent KDM5 histone demethylase (Sowter
et al., 2003; Cheng et al., 2014). Explicitly, human monocytes
5 Epigenetic, metabolic, and immune exposed to β-glucan will have higher concentrations of
crosstalk α-KG-derived metabolites and lower activity of
KDM5 demethylases, which is associated with less
5.1 Principles linking cancer metabolism, H3K4me3 demethylation and higher gene expression
epigenetics, and immunity (Fanucchi et al., 2021). Overall, the induction,
maintenance, and regulation of “trained immunity” is
In the traditional viewpoint, immunological memory is a unique based on the complex interplay between epigenetics and
feature of the adaptive immune system (Netea et al., 2020a). metabolism.

Chen et al. 10.3389/fphar.2022.935536
TABLE 7 Ongoing clinical trials of combined anti-epigenetic drugs and immune checkpoint inhibitors.
Identifier Start year Combination therapy Conditions Phase Enrollment
DNMT inhibitors Checkpoint inhibitor
NCT02608437 2015 Guadecitabine Ipilimumab Metastatic melanoma I 19

NCT02530463 2015 Azacitidine Ipilimumab/Nivolumab MDS/Leukemia II 160
NCT02957968 2016 Decitabine Pembrolizumab Breast cancer II 32
NCT02890329 2016 Decitabine Ipilimumab MDS/AML I 48
NCT02664181 2017 Decitabine Nivolumab NSCLC II 13
NCT03094637 2017 Azacitidine Pembrolizumab High-risk MDS II 37
NCT03264404 2017 Azacitidine Pembrolizumab Pancreas cancer II 31
NCT03019003 2017 Azacitidine Durvalumab Head and neck cancer I/II 13
NCT03308396 2017 Guadecitabine Durvalumab Kidney cancer Ib/II 57
NCT04510610 2019 Decitabine Camrelizumab Hodgkin lymphoma II/III 100
NCT04353479 2020 Decitabine Camrelizumab AML II 29
Identifier Start Year Combination Therapy Conditions Phase Enrollment
HDAC Inhibitors Checkpoint Inhibitor
NCT02616965 2015 Romidepsin Brentuximab vedotin T-cell lymphoma I 27

NCT03024437 2017 Entinostat Atezolizumab Renal cancer I/II 72
NCT03848754 2019 Pracinostat Gemtuzumab ozogamicin AML I 14
NCT03903458 2019 Tinostamustine Nivolumab Advanced melanoma IB 21
NCT03820596 2019 Chidamide Sintilimab NK/T-cell lymphoma I/II 50
NCT04651127 2020 Chidamide Toripalimab Cervical cancer I/II 40
NCT04562311 2020 Chidamide Tislelizumab Bladder cancer II 43
KMT6A Inhibitor Checkpoint Inhibitor
NCT03525795 2018 CPI-1205 Ipilimumab Advanced solid tumor I 24

NCT03854474 2019 Tazemetostat Pembrolizumab Bladder cancer I/II 30
KDM1A inhibitor Checkpoint Inhibitor
NCT02712905 2016 INCB059872 Nivolumab Hematologic tumor I/II 116

NCT02959437 2017 INCB059872 Pembrolizumab Hematologic tumor I/II 70
MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; NSCLC, non-small cell lung cancer.
Apart from trained immunity, the crosstalk of metabolism and epigenetic remodeling (Liu et al., 2017). Specifically,
epigenetics has been reported in T cell (Bailis et al., 2019) and H3K27me3 is a repressive epigenetic marker that downregulates
macrophage activation (Liu et al., 2017). A recent study has shown the expression of M2 macrophage marker genes (Ishii et al., 2009). It
that both mitochondrial citrate export and malate-aspartate shuttle is notable Jmjd3 is a crucial enzyme for demethylation of H3K27
favor histone acetylation and influence the expression of specific (Satoh et al., 2010). α-KG derived from glutamine metabolism could
genes involved in T cell activation (Bailis et al., 2019). Also, a facilitate epigenetic changes in a Jmjd3-dependent demethylation of
research figured out α-KG produced from glutamine metabolism H3K27 on the promoters of M2-specific marker genes (Bailis et al.,
orchestrates M2 macrophage activation by Jmjd3-dependent 2019). This result indicates α-KG and Jmjd3 synergistically

Chen et al. 10.3389/fphar.2022.935536
FIGURE 3
The crosstalk between metabolism and epigenetics in tumorigenesis.
promotes macrophage activation. Consequently, an attractive associated antigen presentation, activation of DC cells,
strategy is to modulate glutamine metabolism to harness suppression of T cell exhaustion. Similar changes in TME
macrophage-mediated immune responses. are also observed in tumor tissues treated with other agents,
such as inhibitors of KMT6A (EZH2), KDM1A (LSD1),
PRMT5, and BET proteins (Hemmings and Restuccia, 2012;
5.2 Rational for novel immunotherapy- Kikuchi et al., 2015; Garcia and Shaw, 2017; Herzig and Shaw,
based combinations 2018; Hoxhaj and Manning, 2020). Consequently, given that
epigenetic drugs boosting antitumor immune response,
Cancer immunotherapy is rapidly developing in various immune checkpoint blockade therapies (ICBTs) and
research settings, including CAR-T cell therapy, immune epigenetic-based inhibitors exert synergistic functions to
checkpoint inhibitors, and adoptive transfer of tumor sensitize less-immunogenic tumors and prevent both
infiltrating lymphocytes (Rosenberg et al., 1988; Zhao et al., primary and acquired resistance (Zhang et al., 2020).
2005; Robbins et al., 2011; Rosenberg et al., 2011; Rosenberg, There are numerous ongoing clinical trials summarized in
2012; Topalian et al., 2012; Maude et al., 2014). An innovative Table 7.
strategy is the combination of immunotherapy with either Metabolism can be modulated in vivo to govern anti-tumor
epigenetic inhibitors or metabolic inhibitors, or a triple T cell longevity and functionality, which determines the efficacy
combination of them. of immunotherapy (Chang and Pearce, 2016; O’Neill et al., 2016).
Epigenetics and immunology are both fast-developing fields The modulation of T cell metabolism is a promising strategy to
in cancer biology. Recent evidence provides unique enhance or suppress immune response (O’Sullivan and Pearce,
opportunities to combine epigenetics-based drugs with 2015), as the characteristics of T cells are critical to determine
immunotherapy (Zhang et al., 2020). Epigenetic-based drugs clinical outcomes (Klebanoff et al., 2012). Several advances have
include four pan-HDAC inhibitors and two DNMT inhibitors been made in preclinical models. For example, when treating
approved by FDA before 2020 (Knutson et al., 2012; Yu et al., vascularized melanoma, limiting the ability of T cells engaged in
2017). These agents are able to change the immunosuppressive glycolysis through suppression of hexokinase by 2-DG could
tumor microenvironment and increased tumor-infiltrating ultimately leads to enhanced anti-tumor efficacy (Sukumar et al.,
lymphocytes (Yanagida et al., 2001; Wang L. et al., 2010; Li 2013). Additionally, metabolic reprogramming occurs in other
et al., 2013; Anwar et al., 2018), leading to enhanced tumor- immune cells within tumor microenvironment, such as

Chen et al. 10.3389/fphar.2022.935536
macrophages and dendritic cells (DCs). One research (Yan et al., factors mediating the tumorigenic activity of oncometabolites
2021) put forward strategies to enhance cancer immunotherapy remains largely unknown. Thirdly, enzymatic parameters, such as
by manipulating metabolism reprogramming. For example, CB- Km, Vmax, and allosteric and inhibitory binding constants, constitute
839 is a glutaminase inhibitor that has been explored in the basic element of the biochemistry (Reid et al., 2017). It is difficult
numerous clinical trials with or without the combinations of to define physiological conditions in which the concentration
immunotherapy (Cerezo and Rocchi, 2020). Acetyl-CoA dynamics of substrates and co-factors causally underlie an
acetyltransferase 1 (ACAT1) inhibitors could enhance the alteration of chromatin status. Discrepancies exist between artificial
activity of CD8+ T cells and reduce the inflammatory culture in vitro and physiological environment in vivo (Davidson et al.,
response. Hence, ACAT1 might be a potential target to 2016). Another complexity is the precise input of metabolism into
optimize immunotherapy (Yang et al., 2016; Huang L. H. chromatin modifications, as both activation and suppression of
et al., 2018; Bi et al., 2019). Indoleamine 2,3-dioxygenase histone marks need metabolites. For instance, how to predict the
(IDO) is responsible for the conversion of tryptophan to changes of SAM level establish the overall chromatin state and
kynurenine in tumors. Blocking IDO can decrease Treg cells epigenetic phenotype. Additionally, though a bunch of metabolic
and preserve the functionality of T cells. Combination of IDO enzymes function in nucleus have been identified, their individual
inhibitors (epacadostat) and immune checkpoint inhibitor contribution to epigenetic alterations was less defined. Robust
(pembrolizumab) has been shown safe enough in clinical experimental methods are needed to obtain accurate
trials, though its efficacy needs further investigation measurements of metabolites in specific cellular domain. Despite
(Prendergast et al., 2017; Komiya and Huang, 2018; Long much interest in targeting both metabolism and epigenetics, poorly
et al., 2019). In summary, glutamine, acetyl-CoA understood layers that whether these two hallmarks confer
acetyltransferase 1 (ATAC1), indoleamine 2,3-dioxygenase dependencies in tumors synergistically still exist.
(IDO), lactate, and Toll-like receptors (TLRs) are likely to be In-depth connection between oncogenic signaling,
considered as novel “metabolic checkpoints”, targeting of which metabolism, epigenetics, and immunity in cancer would
could assist immune cells to achieve better anti-tumor effect. facilitates effective designing of novel targeted drugs, which is
Noteworthily, epigenetic, metabolism, and immune crosslink in the premise of precision medicine. It is anticipated that multiple
germinal-cancer-derived B-cell lymphomas (GCB) uncover a combination therapies hold opportunities to improve care of
rational triple combination therapy (Serganova et al., 2021). GCB cancer patients. Nevertheless, several outstanding challenges will
lymphoma is significantly heterogenous based on genetic, epigenetic, be the major goal of future study.
and clinical characteristics. Epigenetic dysfunction, such as gain-of-
function mutations of EZH2 and loss-of-function mutations of
CREBP and EP300, disrupts the normal biological link between Author contributions
lymphoma cells and immune TME, and motivates immune evasion
in GCB lymphoma. Also, lymphoma metabolism adaptions might YQ designed the study and reviewed the manuscript. CC and
aggravate immunosuppression, leading to poorly infiltrated effector ZW participated in the study design and wrote the original draft
T-cell. Considering the impacts of cancer metabolism on epigenetic of the manuscript. CC was mainly responsible for the design of
modifier and immune microenvironment, triple combination tables and figures. All authors agreed to the submission of the
therapy is a logic and feasible strategy for future treatment. final manuscript.
6 Perspectives Conflict of interest

As reviewed, epigenetics and metabolism are highly The authors declare that the research was conducted in the
interconnected in a reciprocal manner (Figure 3). Such a absence of any commercial or financial relationships that could
relationship is accentuated by the reversibility of both be construed as a potential conflict of interest.
processes (Henikoff and Matzke, 1997). A major goal in
exploring metabolism-dependent epigenetic modifications is
the hope of identifying novel targets for cancer therapy. Publisher’s note
However, some aspects pertaining to metabolic-epigenetic axis
in cancers remain poorly understood. All claims expressed in this article are solely those of the
Firstly, tumor heterogeneity is a major challenge that limits our authors and do not necessarily represent those of their affiliated
understanding (Hensley et al., 2016). Inconsistent metabolic organizations, or those of the publisher, the editors and the
phenotypes were observed in various tumor tissues. Hence, tumor reviewers. Any product that may be evaluated in this article, or
heterogeneity allows cancer cells to escape the deleterious attacks of claim that may be made by its manufacturer, is not guaranteed or
inhibitors (Thakur and Chen, 2019). Secondly, the downstream endorsed by the publisher.

Chen et al. 10.3389/fphar.2022.935536
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PUBLISHED 22 July 2022

Frontiers in Pharmacology 01 frontiersin.org

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TABLE 1 Fundamental interface of metabolism and epigenetics.

Metabolism pathway Metabolic enzyme Metabolites Epigenetic enzyme Epigenetic regulation

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Epigenetic Examples Substrates or Co-factors Mechanisms

DNA methylation and demethylation

DNA DNMTs SAM/SAH (methionine cycle) Methyl donors for methyltransferases

Histone acetylation and deacetylation

Histone HATs Acetyl-CoA (TCA cycle/acetate) Acetyl donors for acetyltransferases

Histone methylation and demethylation

Histone kinase AMPK ATP/AMP Phosphate donors for protein kinase

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TABLE 3 The effect of oncometabolites on epigenetic dysfunction and immunosuppression.

Oncometabolite Metabolic Epigenetic Immunosuppressive Malignancies References

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3 Epigenetic events contribute to 3.2.2 SIRT7

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TABLE 4 Reversal of epigenetic dysfunction by targeting metabolism.

Target Metabolic Pharmacological Mechanism Indications References

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TABLE 5 Reversal of metabolism reprogramming by targeting epigenetics.

Inhibitors Target enzyme Pharmacological Mechanism Indication References

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Identiﬁer Start year Combination therapy Conditions Phase Enrollment

Anti-epigenetics Anti-metabolism drug

NCT02719574 2016 Azacitidine FT-2102 AML/MDS I/II 336

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Identiﬁer Start year Combination therapy Conditions Phase Enrollment

DNMT inhibitors Checkpoint inhibitor

NCT02608437 2015 Guadecitabine Ipilimumab Metastatic melanoma I 19

Identiﬁer Start Year Combination Therapy Conditions Phase Enrollment

HDAC Inhibitors Checkpoint Inhibitor

NCT02616965 2015 Romidepsin Brentuximab vedotin T-cell lymphoma I 27

Identiﬁer Start Year Combination Therapy Conditions Phase Enrollment

KMT6A Inhibitor Checkpoint Inhibitor

NCT03525795 2018 CPI-1205 Ipilimumab Advanced solid tumor I 24

Identiﬁer Start Year Combination Therapy Conditions Phase Enrollment

KDM1A inhibitor Checkpoint Inhibitor

NCT02712905 2016 INCB059872 Nivolumab Hematologic tumor I/II 116

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6 Perspectives Conﬂict of interest

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