BBA - Reviews on Cancer 1878 (2023) 188837

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BBA - Reviews on Cancer

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Review

Acetyl-CoA regulates lipid metabolism and histone acetylation modification

in cancer
Weijing He a, b, Qingguo Li a, b, *, Xinxiang Li a, b, *
a
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
b
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

A R T I C L E I N F O A B S T R A C T

Keywords: Acetyl-CoA, as an important molecule, not only participates in multiple intracellular metabolic reactions, but
Acetyl-coenzyme A (acetyl-CoA) also affects the post-translational modification of proteins, playing a key role in the metabolic activity and
Lipid metabolism epigenetic inheritance of cells. Cancer cells require extensive lipid metabolism to fuel for their growth, while also
Histone acetylation
require histone acetylation modifications to increase the expression of cancer-promoting genes. As a raw material
Cancer
for de novo lipid synthesis and histone acetylation, acetyl-CoA has a major impact on lipid metabolism and
histone acetylation in cancer. More importantly, in cancer, acetyl-CoA connects lipid metabolism with histone
acetylation, forming a more complex regulatory mechanism that influences cancer growth, proliferation,
metastasis.

1. Introduction 2. Acetyl-CoA

Cancer initiation and progression are often accompanied by drastic 2.1. Basics of acetyl-CoA
metabolic changes as well as alterations in multiple protein post-
translational modifications. [1,2] Among these changes and alter­ Acetyl-CoA is formed by the acetylation of coenzyme A, which
ations, lipid metabolism and histone acetylation modification have consists of an acetyl group linked to a cysteine residue of coenzyme A
received much attention because of their critical roles for the life ac­ through a high-energy thioester bond. [7] Acetyl-CoA is mainly
tivities of tumor cells. [3,4] Whereas acetyl-CoA serves as an interme­ distributed in mitochondria, cytosol and nuclear solute in cells. See
diate product and signaling molecule of many metabolic pathways, not (Fig. 1) [8] In terms of metabolism, the role of acetyl-CoA is mainly
only as a substrate for fatty acid synthesis, but also provides raw ma­ viewed from its different locations. In mitochondria, acetyl-CoA reacts
terials for histone acetylation modification with its acetyl groups, which with oxaloacetic acid to produce citric acid, thus participating in
forms a bridge between lipid metabolism and histone acetylation tricarboxylic acid (TCA) cycle. [9] In the cytoplasm, acetyl-CoA is
modification. [5,6] However, how acetyl-CoA affects cancer through involved in the synthesis of fatty acids and cholesterol. [10] In terms of
lipid metabolism and histone acetylation in cancer is not fully under­ epigenetics, acetyl-CoA can modify the post-translation protein and
stood, nor is the role of acetyl-CoA in the relationship between lipid provide raw materials for the acetylation of lysine in the protein. In
metabolism and histone acetylation. A review of the above issues will particular, it can freely enter the nucleus through nuclear pores and
help us better understand the role of acetyl-CoA in cancer, link meta­ acetylate histones in the nucleus. [11] Histone acetylation regulates the
bolism with epigenetics, and provide new ideas for cancer treatment. expression of genes, thereby affecting a series of life activities of cells,
This review will start with a brief overview of acetyl-CoA, followed by such as cell metabolism, growth, proliferation, autophagy, etc. [12–14]
changes of acetyl-CoA in cancer its regulation of lipid metabolism and
histone acetylation. At the end, the connection established by acetyl-
CoA between lipid metabolism and histone acetylation will be 2.2. Production and consumption of acetyl-CoA
addressed.
Acetyl-CoA cannot directly penetrate the inner mitochondrial
membrane and has the characteristics of compartmentalization. See

* Corresponding author at: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
E-mail addresses: [email protected] (Q. Li), [email protected] (X. Li).

https://doi.org/10.1016/j.bbcan.2022.188837
Received 11 July 2022; Received in revised form 10 November 2022; Accepted 12 November 2022
Available online 17 November 2022
0304-419X/© 2022 Published by Elsevier B.V.
W. He et al. BBA - Reviews on Cancer 1878 (2023) 188837

Fig. 1. The main relationship between acetyl-CoA metabolism, lipid metabolism and histone acetylation in tumor cells.
The uptake of acetate by tumor cells is increased, and in the cytoplasm, acetate can generate acetyl-CoA under the catalysis of ACSS2. Citrate can enter the cytoplasm
from mitochondria and generate acetyl-CoA under the catalysis of ACLY. Acetyl-CoA in the cytoplasm, on the one hand, generates malonyl-CoA under the catalysis of
ACC, thereby participating in the de novo synthesis of fatty acids, and on the other hand, it can enter the nucleus for histone acetylation modification. Acetate and
citrate can enter the nucleus as raw materials for the production of acetyl-CoA. ACSS2 is a bidirectional enzyme that can decompose acetyl-CoA to produce acetate
when acetyl-CoA levels are excessive, thereby achieving a steady state of acetyl-CoA. PDC is found in the mitochondria and nucleus. PDC in mitochondria converts
pyruvate to acetyl-CoA, which participates in TCA cycle. The acetyl-CoA catalyzed by PDC in the nucleus is mainly used for histone acetylation modification. AT-1
can transport acetyl-CoA in the cytoplasm to the endoplasmic reticulum, thereby changing the concentration of acetyl-CoA in the cytoplasm and affecting histone
acetylation and lipid metabolism.
Abbreviation: ACLY: ATP citrate lyase; PDC: Pyruvate dehydrogenase complex; ACSS2: Acyl-CoA synthetase short-chain family member 2; ACC: Acetyl-CoA
carboxylase.

(Fig. 2) [15] Therefore, the production and consumption of acetyl-CoA deprivation leads to Adenosine 5′ -monophosphate (AMP)-activated
can be explained from the perspective of different subcellular localiza­ protein kinase (AMPK)-mediated phosphorylation of ACSS2 at S659,
tion. Acetyl-CoA is mainly produced in mitochondria and cytoplasm, which causes ACSS2 to move toward the nucleus, increasing acetyl -CoA
and it can also be produced ectopic in the nucleus. [16] In the inner production in the nucleus and increasing histone acetylation. [25] In
mitochondrial membrane, pyruvate is catalyzed by pyruvate dehydro­ mitochondria, glutamine can be catalyzed by Glutaminase-1/2 (GLS1/2)
genase complex (PDC) to form acetyl-CoA, and the formed acetyl-CoA to produce glutamate, which is involved in the production of α-keto­
participates in the TCA cycle. [17] In the mitochondrial matrix, acyl- glutarate, and glutamine-derived α-ketoglutarate can be catalyzed by
CoA is generated via fatty acid β-oxidation (FAO) to acetyl CoA. [18] isocitrate dehydrogenase 1/2 (IDH1/2) to produce isocitrate, which
Branched-chain amino acids can first be catalyzed by the cytoplasmic then generates citrate involved in the synthesis of acetyl-CoA. Intra­
enzyme branched-chain amino acid transaminase 1 (BCAT1) to form cytoplasmic glutamine can also be involved in the generation of citrate,
branched-chain α-keto acids, which enter the mitochondrial matrix and which leads to the synthesis of acetyl-CoA. [26,27] Notably, PDC can
catalyzed by mitochondrial branched-chain α-keto acid dehydrogenase catalyze pyruvate within the nucleus to produce acetyl-CoA. [28]
(BCKD) complex to produces acetyl-CoA. [19,20] In the cytoplasm, Nucleolar glycogen can also provide pyruvate by catabolism in the nu­
there are two very critical enzymes that play a major role in the pro­ cleus, leading to a carbon source for Acetyl CoA. In human non-small cell
duction of acetyl-CoA, namely ATP citrate lyase (ACLY) and acyl-CoA lung cancer (NSCLC), ubiquitination and translocation of glycogen
synthetase short-chain family member 2 (ACSS2). ACLY can convert phosphorylase (GP) by E3 ubiquitin ligase malin results in the catabo­
citrate to acetyl-CoA, citrate can be derived from the transport of citrate lism of glycogen to fructose 6-phosphate (F6P), 3-phosphoglycerate
pyruvate cycle, or from the catalytic generation of cytosolic α-ketoglu­ (3PG), and pyruvate. Pyruvate through effect of PDH generates Acetyl
tarate. [21] ACSS2 can convert cytosolic acetate to acetyl-CoA. [22] CoA, which increases histone acetylation in the nucleus. [29–31]
Acetate can be derived from extracellular uptake, glucose metabolism. Acetyl-CoA consumption is mainly due to its participation in the TCA
Deacetylation of proteins can also provide a small fraction of acetate. cycle in the mitochondria and anabolic metabolism in the cytosol, such
[23] When ACLY is deficient, the compensatory expression of ACSS2 is as fatty acid synthesis, steroid synthesis. [32] The synthesis of some
increased by the regulation of mTOR complex 2 (mTORC2), which amino acids also requires the participation of acetyl-CoA. [33] The
makes the intracellular synthesis of acetyl-CoA from the source of process of producing fatty acids from acetyl-CoA is called de novo fatty
glucose to the source of acetate. [24] In addition, the function of ACLY is acid synthesis (FAS). In this process, acetyl-CoA is first catalyzed by
restricted during glucose deprivation, while ACSS2 becomes the main acetyl-CoA carboxylase (ACC) to generate malonyl-CoA, and then
enzyme for intracellular acetyl CoA synthesis, especially since glucose malonyl-CoA is catalyzed by fatty acid synthase (FASN) to form fatty

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W. He et al. BBA - Reviews on Cancer 1878 (2023) 188837

Fig. 2. Acetyl-CoA metabolism in cells.

In cells, acetyl-CoA has multiple metabolic pathways. Sources of acetyl-CoA generation include TCA cycle, β-oxidation, acetate, citrate, pyruvate, glutamine, and
histone deacetylation. Acetyl-CoA consumption includes fatty acid synthesis, and histone acetylation.
Abbreviation: ACLY: ATP citrate lyase; PDC: Pyruvate dehydrogenase complex; ACSS2: Acyl-CoA synthetase short-chain family member 2; ACC: Acetyl-CoA
carboxylase; FASN: Fatty acid synthase; IDH1/2: Isocitrate dehydrogenase 1/2, GLS1/2: Glutaminase-1/2; KATS: K (lysine) acetyltransferase; HDAC: Histone
deacetylase.

acids. [34] In the cytoplasm and nucleus, another important consump­ surtuins-3 (SIRT3) depletion reduces intracellular acetyl-CoA levels,
tion pathway of acetyl-CoA is involved in the acetylation of proteins, which in turn induces autophagy and death to inhibit the formation of
especially for histone acetylation. [35] Histones are proteins in the nu­ diffuse large B-cell lymphoma. [45] Nutritionally, glucose restriction in
cleus that bind to chromosomal DNA, and there are five types of pro­ cultured tumor cells reduced cellular acetyl-CoA content and total pro­
teins: H1, H2A, H2B, H3, and H4. Histones can complete acetylation tein acetylation, which could be rescued by exogenous acetate supple­
modification by consuming acetyl-CoA under the effects of K (lysine) mentation. [40] Interestingly, the expression of ACSS2, which catalyzes
acetyltransferase (KAT) or histone deacetylase (HDAC), thereby regu­ acetate to acetyl-CoA, was increased in many cancers, suggesting that
lating gene replication, transcription, and expression. [36,37] cancer cells have increased acetate utilization. [46,47] Among these
cancers, colorectal cancer had the highest elevated ACSS2 expression.
[48] It is possible that gut microbe-derived acetate helps cancer develop.
2.3. Altered acetyl-CoA metabolism in cancer [49] Bacteroides and Bifidobacterium microbiota ferment dietary fiber
to produce acetate [50]. It has also been demonstrated that gut microbes
Acetyl-CoA metabolism in cancer is mainly affected by cancer- produce acetate via fructose. [51]
related genes and nutrients (eg, glucose, acetate). See (Fig. 3) [38,39] PDC plays an important role in acetyl-CoA metabolism in cancer.
In terms of cancer-related genes, the up-regulation of Serine/threonine- PDC is found in the mitochondria and nucleus and utilizes pyruvate as a
protein kinase 1 (AKT1) can increase the phosphorylation of ACLY, substrate to synthesize acetyl-CoA. [52] PDC in the mitochondria pri­
thereby increasing the production of acetyl-CoA. Activation of kirsten marily links glucose metabolism to the TCA cycle and in the nucleus
rat sarcoma viral oncogene (KRAS) also leads to increased production of mainly generates acetyl-CoA, which is used for histone acetylation. PDC
acetyl-CoA, which has been shown to stimulate AKT1 signaling in is directly regulated by pyruvate dehydrogenase kinase (PDK), which
pancreatic cells. [40,41] Cellular-myelocytomatosis viral oncogene (c- can phosphorylate PDC and cause its inactivation. [53] In tumor cells,
Myc) activation also promotes the production of acetyl-CoA [42]. PDK expression rises, causing PDC inactivation and thus more pyruvate
Upregulation of human epidermal growth factor receptor-2 (HER2) or to be reduced to lactate. Moreover, elevated PDK expression is closely
epidermal growth factor receptor (EGFR) in breast cancer increases the associated with poor prognosis of tumors. [53] In tumor cells, most of
synthesis of acetyl-CoA to provide the raw material for fatty acid pro­ pyruvate is converted to lactate, and a small proportion of pyruvate
duction. [43] It is worth mentioning that there are also some genes participates in the TCA cycle, resulting in reduced acetyl-CoA produc­
whose expression can inhibit the production of acetyl-CoA, but still tion in the mitochondria. [54–56] Therefore, the role of PDC in the
promote tumor growth. For example, in colorectal cancer, thymi­ nucleus of tumor cells for acetyl-CoA synthesis is particularly vital in this
ne–guanine-interacting factor (TGIF) can inhibit ACSS2, possibly by situation. In cancer cells, due to hypoxia and nutrient limitation, the
promoting the expression of GLUT1 (glucose transporter type 1) for expression of PDK in mitochondria increases, which inactivates PDC in
metabolic reprogramming and aiding tumor development. [44]

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W. He et al. BBA - Reviews on Cancer 1878 (2023) 188837

Fig. 3. The factors that affect Acetyl-CoA metabolism in cancer.

Acetyl-CoA metabolism is affected by many factors in cancer. These factors include cancer-related genes, nutrition, metabolic enzymes, hypoxia, PDC and PDK, NAA
signaling pathways.
Abbreviation: ACLY: ATP citrate lyase; PDC: Pyruvate dehydrogenase complex; ACSS2: Acyl-CoA synthetase short-chain family member 2; ACC: Acetyl-CoA
carboxylase; PDK: Pyruvate dehydrogenase kinase; AKT1: Serine/threonine-protein kinase 1; KRAS: Kirsten rat sarcoma viral oncogene; HER2: Human epidermal
growth factor receptor-2; C-MYC: Cellular-myelocytomatosis viral oncogene; EGFR: Epidermal growth factor receptor; mTORC2: mTOR complex 2;

mitochondria, and this promotes the movement of PDC in the mito­ breast cancer and lung cancer. [67,68] John R. Moffett et al. put forward
chondria toward the nucleus. These mitochondrial-derived PDC elevates the hypothesis that NAA can be transported into the nucleus to generate
acetyl CoA levels in the nucleus, leading to increased acetylation of acetate under the effect of Aspartoacylase (ASPA), and then acetate is
histones H2B, H3 and H4. [57] Taking prostate cancer as an example, generated under the action of ACSS2 to acetyl-CoA, which acts on the
mitochondrial PDC provides citrate to promote cellular lipid synthesis, acetylation of specific transcription factors. [69] This NAA signaling
and nucleolar PDC, by increasing acetyl-CoA production, can promote pathway may be an important regulation of acetyl-CoA in cancer under
acetylation of H3K9, increase ACLY expression, and increase fatty acid metabolic stress.
synthesis, thereby maintaining prostate carcinogenesis. [58]
Hypoxia is also one of the factors affecting acetyl-CoA metabolism in 3. Acetyl-CoA metabolism regulates lipid metabolism in cancer
cancer. Due to the rapid proliferation and growth of tumor cells, some of
them in the tumor microenvironment will be in a state of hypoxia, and The role of lipid metabolism in cancer is very important, and the
hypoxia causes the transcription factor-induced hypoxia factor (HIF) in genes related to lipid metabolism can also be used as indicators to pre­
the cells to be activated. [59] HiF-1α upregulates the expression of dict cancer prognosis. [70] The de novo synthesis of fatty acids in lipid
GLUT1, which increases the uptake of glucose by cancer cells, and metabolism is particularly critical, which is key to the growth of many
glucose has a certain effect on the maintenance of acetyl-CoA. [60] At types of cancer. During tumor cell growth and proliferation, fatty acids
the same time, hypoxia will also increase the expression of ACSS2 and can be used to form membrane structures, provide energy, and
increase the transfer of ACSS2 from the cytoplasm to the nucleus, contribute to resistance against oxidative stress. [71] Acetyl-CoA mainly
increasing the acetyl-CoA generated in the nucleus. regulates lipid metabolism by participating in the de novo synthesis of
And this process increases the acetylation of HIF-2α, which is fatty acids. Acetyl-CoA is catalyzed by ACSS2 and ACLY on the one hand,
important for tumor cell proliferation. [61] Under hypoxic conditions, and carboxylated to malonyl-CoA by ACC on the other hand. These three
the expression of Glis1 is increased in various cancers, and Glis1 can enzymes play a very important role in acetyl-CoA metabolism in cancer.
increase cellular acetyl-CoA levels through metabolic reprogramming. The uptake of acetate by cancer cells increases, and the up-regulated
[62] Similarly, the increased utilization of glutamine in cancer cells to ACSS2 can promote the production of acetyl-CoA, which is mainly used
supplant acetyl-CoA and promote lipid synthesis. [63–65] for fatty acid synthesis. [72] ACSS2 is a bidirectional enzyme that con­
There is an interesting hypothesis that there may be a new pathway verts intracellular acetyl-CoA to acetate, especially under hypoxic con­
in cancer that affects the metabolism of acetyl-CoA, the “N-acetylas­ ditions with high intracellular acetyl-CoA concentrations in cancer cells.
partate (NAA) signaling pathway.” The acetylated form of aspartate, [73] This indicates that the bidirectionality of ACSS2 has a certain effect
previously thought to be present only in the nervous system, was later on the homeostasis of acetyl-CoA in cancer cells, thereby affecting the
found to be elevated in ovarian cancer, shattering the previous view synthesis of fatty acids in cancer cells. It is worth mentioning that ACSS2
[66]. Later studies found that NAA actually has higher concentrations in can stabilize the oncoprotein interferon regulatory factor 4 (IRF4) to

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W. He et al. BBA - Reviews on Cancer 1878 (2023) 188837

promote myeloma under obesity stress. [74] nuclear ACLY activity. [92] In the process of hepatocyte metastasis, the
ACLY can convert citrate to acetyl-CoA, establishing a link between down-regulation of acyl-CoA thioesterase 12 (ACOT12) promoted the
glycolysis and lipid metabolism. The expression and activity of ACLY are production of intracellular acetyl-CoA and increased H3 acetylation. H3
found to be increased in many tumors, especially in hepatocellular acetylation in turn increases twist family BHLH transcription factor 2
carcinoma (HCC). [75,76] Knockdown of ACLY can also reduce cancer (TWIST2) expression, which increases EMT (epithelial-mesenchymal
stemness in a variety of cells. [77] In adenocarcinoma cells, knockdown transition) to promote tumor metastasis. [93]
of ACLY inhibits the metabolism of glucose to lipids. [78] In nasopha­ Mitochondrial-derived citrate can also affect histone acetylation by
ryngeal carcinoma, ACLY can bind to LncRNA TINCR to avoid degra­ generating acetyl- CoA. [94,95] In mitochondria, excess citrate derived
dation, maintain the intracellular acetyl-CoA level, promote lipid from the TCA cycle can enter the cytoplasm via mitochondrial citrate
synthesis, and enhance tumor progression. [79] In colorectal cancer, carriers (CIC) and generate acetyl-CoA catalyzed by ACLY. [96] If ACLY
ACLY in CAF increases the level of intracellular acetyl-CoA under the is inhibited, citrate accumulation in the cytoplasm will suppress the
action of exosomal HSPC111 secreted by cancer cells, promotes lipid activity of the glycolytic enzymes phosphofructokinase 1 (PFK1) and
metabolism, and increases liver metastasis of colorectal cancer. [80] phosphofructokinase 2 (PFK2), thus reducing glycolysis in tumor cells
ACC1 is highly expressed in various cancers, such as breast cancer, and leading to apoptosis. [97,98] Therefore, citrate is maintained at low
liver cancer, and gastric cancer. [81] But the role of ACC1 in the concentration levels in the cytoplasm of cancer cells. [99] The main
mechanism of cancer development seems to be two-sided. In breast metabolic pathway of citrate in the cytoplasm is mainly to generate
cancer, phosphorylation of ACC1 increases acetyl-CoA levels, thereby acetyl-CoA. In addition to participating in fatty acid synthesis, acetyl-
increasing protein acetylation levels, especially Smad2 acetylation and CoA generated by mitochondrial-derived citrate in the cytoplasm can
EMT (epithelial-mesenchymal transition), which promotes breast cancer influence histone acetylation. [100,101] For example, in macrophages,
metastasis. [82] In liver cancer, however, ACC1 was inhibited by ACLY catalyzes the conversion of mitochondrial-derived citrate to
phosphorylation or ND-654 treatment, reducing lipid production and acetyl-CoA, promoting histone acetylation at certain M2 gene pro­
tumor growth. [83] In prostate cancer (PCa), valproic acid (VPA) can moters. [102] Similarly, in myoblasts, conversion of citrate to acetyl
inhibit the expression level of ACC1 in PC-3 and LNCaP cells. This re­ coenzyme A by ACLY increased H3 acetylation at the myogenic differ­
duces lipid accumulation by cells through the CCAAT/enhancer binding entiation antigen (MyoD) promoter. [103] In cancer, the oncogenic gene
protein alpha (C/EBPα) and sterol regulatory element binding protein 1 Akt promotes the conversion of citrate to acetyl-CoA by promoting the
(SREBP-1) pathways. [84] In KRAS-mutated pancreatic cancer cells, phosphorylation and activation of ACLY, which increases histone acet­
eicosapentaenoic acid (EPA) reduced ACC1 expression in SUIT-2 cells ylation in prostate tumor cells. [104] In melanoma cells, mitochondrial-
and decreased ACC1-mediated lipid de novo synthesis, thus inhibiting derived citrate catalyzed by ACLY to acetyl-CoA increases histone
tumor cell growth and survival. [85] However, in acute myeloid leu­ acetylation at the melanocytic-lineage oncogenic factor (MITF) locus,
kemia (AML), stabilization of ACC1 decreases acetyl-CoA levels, pro­ which promotes tumor growth. [105] Because of such effects of citrate,
motes fatty acid synthesis, and increases intracellular reactive oxygen oncology therapies targeting citrate are also emerging as a new treat­
species (ROS) levels, which leads to the suppression of AML progression. ment strategy. [106]
[86] In spite of mitochondrial-derived citrate, mitochondria themselves
In general, the regulation of lipid metabolism in tumors by acetyl- also have an impact on histone acetylation, such as mitochondrial DNA
CoA metabolism is mainly affected by three enzymes, ACSS2, ACLY (mtDNA). [107,108] MtDNA copy number has been found to affect
and ACC. Expression of these three enzymes is elevated in a variety of histone acetylation in cancer by altering intracellular acetyl CoA level
cancers. The increased expression of ACSS2 and ACLY was beneficial to and influencing histone acetyltransferase (HAT)/ histone deacetylase
the production of acetyl-CoA, and the increased expression of ACC was (HADC) activity. [108–110] In colon cancer, the reduction in mtDNA
beneficial to increase the utilization of acetyl-CoA. In cancer, through copy number leads to decreased acetyl-CoA level and HAT activity,
the effect of these three enzymes, acetyl-CoA increases lipid metabolism which in turn reduces intracellular levels of H3K27ac. [111] H3K27ac in
or enhances protein acetylation, which promotes tumor growth. turn is a super-enhancer of the expression of oncogenes such as c-MYC.
[112] So reduced mtDNA copy number suppresses tumor growth.
4. Acetyl-CoA metabolism regulates histone acetylation However, it has also been shown that mtDNA reduction can be mediated
modifications in cancer by heterogeneous ribonucleoprotein A2 (hnRNPA2) to increase acetyl-
CoA level in cells and promote histone acetylation. [113] This may be
The overall intracellular level of acetyl-CoA is positively correlated explained by the specificity of metabolic patterns and mitochondrial
with the level of histone modifications. [87] In the nucleus, a rise in dysfunction in different cancers. [114–116] A variety of tumor types
acetyl-CoA concentration can increase lysine acetyltransferases (KAT) have a reduction in mtDNA copy number relative to adjacent normal
activity to enhance histone acetylation. This regulation of KAT is not tissue, such as bladder, breast, esophageal, kidney, and liver cancers. In
determined by the absolute level of acetyl-CoA, but rather by the ratio of contrast, ovarian, colorectal, and lung adenocarcinomas have increased
acetyl-CoA/acetate, which is due to the inhibition of KAT activity by mtDNA copy number compared to normal tissues. [117] Although the
acetate produced in histone acetylation. [88] Compared to normal cells, exact mechanism of how mtDNA affects histone acetylation currently is
Acetyl-CoA synthesis is increased in the nucleus of cancer cells. Since unclear, it is obvious that the role played by mitochondria in cancer is
ACSS2 and ACLY can reside in the nucleus, acetate and citrate can be increasingly worthy of attention.
converted to acetyl-CoA to enhance histone acetylation. In pancreatic In cancer, the regulation of histone acetylation by acetyl-CoA
ductal adenocarcinoma (PDA), elevated levels of acetyl-CoA lead to metabolism mainly depends on the level of acetyl-CoA, especially the
increased histone acetylation to support tumorigenesis. [89] In AML, level of acetyl-CoA in the nucleus.
AMPK facilitates acetyl-CoA homeostasis and maintains histone acety­ Overall, cancer cells require substantial histone acetylation to sup­
lation and recruits bromodomain 4 (BRD4) to chromatin. [90] In HCC, port their rapid proliferation.
ACLY expression is increased but ACSS2 has no significant change
compared with normal tissues. So XiaowenHu et al. proposed a hypo­ 5. Acetyl-CoA metabolism establishes the connection between
thetical model of the oncogenic acetylome by studying the acetylome of lipid metabolism and histone acetylation in cancer
HCC tumors. The hypothesis is that acetyl-CoA increases histone acet­
ylation through ACLY-dependent migration from mitochondria to the In cancer, both metabolic reprogramming and epigenetic changes
nucleus. [91] In cancer cells, SIRT6 inhibits cell invasion by reducing affect tumor initiation and progression. There is growing evidence that
acetyl-CoA levels and then reducing histone acetylation by inhibiting acetyl-CoA metabolism connects lipid metabolism with histone

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Fig. 4. A basic network between histone acetylation and FAS and FAO through Acetyl-CoA.
Acetyl-CoA establishes a complex regulatory network between histone acetylation and FAS and FAO. This network diagram can be divided into three parts: A is
lipolysis metabolism, B is lipid synthesis metabolism, C is acetyl-CoA and histone acetylation.
Abbreviation: FAS: Fatty acid synthesis; FAO: Fatty acid oxidation; FFA: Free fatty acid; LD: Lipid droplet; DGAT1: Diacylglycerol-acyltransferase 1; ROS: Reactive
oxygen species; ACC1/2: Acetyl-CoA carboxylase 1/2; FASN: Fatty acid synthase; ACSS2: Acyl-CoA synthetase short-chain family member 2.

acetylation in cancer cells. increase H3K9 acetylation levels, leading to enhanced glycolysis and
Abnormal lipid metabolism is a classic feature of cancer metabolism. triglyceride synthesis and reduced FAO. [130,131] However, in view of
In this sense, increased de novo fatty acid synthesis (FAS) is a prominent the heterogeneity among different tumors and within the same tumor,
feature, and fatty acid β-oxidation (FAO) should not be ignored, as it more solid evidence is needed to support that tumors with different lipid
prevents lipid accumulation resulting in lipotoxicity. [4] In a pan-cancer metabolism preferences have specific feature of alterations in histone
(solid tumor) study on lipid metabolism, the expression of fatty acid acetylation.
biosynthesis-related specific genes was found to be upregulated in most Acetyl-CoA establishes a complex regulatory network between his­
cancers, and in contrast, genes for beta-oxidation processes were down- tone acetylation and FAS and FAO. A basic network relationship dia­
regulated in most cancers. [118] This indicates that most tumors prefer gram is shown in the Fig. 4. This network diagram can be divided into
to lipid accumulation. However, prostate cancer and diffuse large B-cell three parts: A is lipolysis metabolism, B is lipid synthesis metabolism, C
lymphoma (DLBCL) of the oxidative phosphorylation subtype tend to is acetyl-CoA and histone acetylation.
use FAO as the dominant bioenergetic pathway. [119,120] Histone From the aspect of altered lipolysis, FAO increases in tumor cells
acetylation in this FAO-preferring cancer appears to present a pattern of under nutrient-deficient conditions, such as during hypoxia and tumor
H3 and H4 hypoacetylation or decreased acetylation levels. For metastasis, to provide energy, antioxidative stress, drug resistance and
example, AcH3 and AcH4 are reduced in prostate cancer compared to maintenance of tumor stemness. [125,132–134] Eoin McDonnell et al.,
normal prostate tissue. [121,122] Prostate cancer cell line PC3 has lower using the 13C carbon tracking technique, found that lipid oxidation
levels of lipid synthesis compared to MCF7 (breast cancer), A549 (lung reprogramming produces acetyl-CoA from octanoate, and these sources
cancer) and PANC1 (pancreatic cancer). [123] Prostate cancer cell line of acetyl-CoA are the main carbon sources for histone acetylation. [129]
DU-145 and PC3 have lower acetylation at the N-terminal lysine 9, 14, In breast cancer, increased FAO results in increased acetyl-CoA, which
18 and 23 of histone H3. [121] The histone H2B of DU-145 is in hypo­ promotes the acetylation of H3, especially H3K27ac. Such increased
acetylation. [124] histone acetylation drives up the expression of EMT-associated genes in
Some tumors exhibit high FAO activity along with increased FAS, breast cancer. [135] EMT contributes to the onset of tumor metastasis.
such as breast cancer, ovarian cancer, lung cancer. [125] These cancers Inhibition of FAO and increased fat storage inhibits EMT and leads to
also appear to present the similar pattern. Basal like, HER-2+ breast tumor conversion to MET. In colon cancer, a high-fat diet promotes FAO
cancer have low to moderate levels of H3K9ac, H3K18ac and H4K12ac. activation, which in turn leads to the growth, proliferation and tumor­
[126] H1K26, H3K9, H3K14 and H4K16 histone acetylation levels are igenesis of intestinal stem cells. [136]
reduced in malignant ovarian cancer. [127] Loss of H4K16 acetylation In the nutrient restricted situation, FAO increases acetyl-CoA gen­
are observed in ovarian epithelial cancer tissues. [128] Non-small cell eration in cancer cells, and the generated acetyl-CoA participates in the
lung cancer (NSCLC) presents low levels of H3K9ac and H4K16ac, which TCA cycle to provide energy for tumor. [137]
positively correlated with tumor recurrence. [129] Hypoacetylation of From the aspect of altered lipid synthesis, in breast cancer, inhibition
H3K9 is probably the feature of tumors preferring FAO. This hypothesis of ACC1 leads to decreased lipid synthesis and increased acetyl-CoA
is supported by the fact that SIRT6-specific deficient livers significantly levels, which raises H3 acetylation and promotes tumor metastasis and

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Fig. 5. A crosstalk of acetyl-CoA between

histone acetylation and lipid metabolism in
cancer.
Acetyl-CoA is in one hand involved in
histone acetylation modification, and on
the other hand is participating in the de
novo synthesis of fatty acids. At the same
time, histone acetylation regulates genes
related to lipid metabolism, lipid meta­
bolism in turn provides a carbon source for
histone acetylation. This crosstalk plays an
important role in tumor growth, prolifera­
tion and metastasis.

recurrence. [138] However, in glioblastoma (GBM), reduced expression Changes in the flux of the acetyl-CoA compartment also have effects
of diacylglycerol-acyltransferase 1 (DGAT1) leads to reduced lipid on lipid metabolism and histone acetylation. As an acetyltransferase A
storage, free fatty acids contribute to increased FAO and accumulation transporter, AT-1/SLC33A1 can transfer acetyl-CoA from the cytoplasm
of excess acetyl- CoA. It increases ROS and apoptosis within cancer cells to the endoplasmic reticulum and play an important role in acetylation
suppressing GBM growth. [139] in the endoplasmic reticulum. Using mouse models expressing different
From the aspect of altered acetyl-CoA and histone acetylation, in levels of AT-1, Inca A. Dieterich et al. found that AT-1 maintains cellular
liver cancer, free fatty acids lead to elevated acetylation of H3K9, H4K8 metabolic crosstalk through changes to the proteome and acetyl prote­
and H4K16, promoting lipid accumulation. [140] Increased acetylation ome. In the model with elevated AT-1 expression, more cytoplasmic
of H3K27 in pancreatic β-cells on a high-fat diet upregulates acetyl-CoA acetyl-CoA was transported to the endoplasmic reticulum. In this case,
acyltransferase 2 (ACAA2) and SLC25A20 expression and promotes the metabolism within the cell changes in a direction that resists this
FAO. In a rat colon cancer progression model, the fish oil and pectin change. That is, when the expression of AT-1 is increased, the level of
combination diet leads to an increase acetylation in H3, which induces acetyl-CoA in the cytoplasm is maintained by reducing adipogenesis.
FAO-related gene expression and promotes tumorigenesis. [141] Under [146] AT-1 may also be a new therapeutic target for the disease. Kelch-
glucose-limited conditions, acetyl-CoA levels were reduced resulting in a like ECH Associated-Protein 1 (KEAP1) mutated lung cancer selectively
reduction in the acetylation of H3 histones. Although the level of histone relies on the Slc33a1/AT-1 gene, and when the AT-1 gene is knocked out
acetylation was reduced, the site of histone acetylation changed. Under in KEAP1-mutated cancer cells, tumor growth is inhibited. [147] How
the effect of the histone acetyltransferase Gcn5, acetylation of histone AT1 plays a role in tumors by altering the levels of acetyl-CoA in
acetylation sites that promote gluconeogenesis and fatty acid oxidation different compartments requires further study.
is increased. [142] Caspase-10 can cleave ACLY, resulting in a decrease Here’s one more thing that has to be mentioned. Upregulation of
in ACLY activity, which reduces acetyl-CoA levels in the nucleus, Prox1 enhances the production of acetyl-CoA dependent on FAO, which
resulting in lower intracellular lipid levels and inhibition of GCN5- is subsequently used by histone acetyltransferase p300 to acetylate
mediated acetylation of histones H3 and H4. This change reduces histones involved in lymphangiogenesis. [148] The contribution of
tumor metastasis capacity. [143] Under hypoxic conditions, human Prox1 to the formation of the lymphatic system makes the cancer more
hepatocellular carcinomas with high ACSS1/2 expression utilize acetate prone to tumor metastases.
to increase acetyl CoA generation, leading to increased acetylation of Overall, changes originating from lipid metabolism or changes
H3K9, H3K27 and H3K56. Such H3 acetylation causes activation of originating from histone acetylation will have certain effects on each
FASN, resulting in improved FAS. [144] This effect enhances tumor other through acetyl-CoA in cancer. Clearly, the homeostasis of acetyl-
survival under hypoxic condition. Interestingly, the acetylation of H3 CoA is crucial for cancer cells to utilize lipid metabolism and histone
and H4 is reduced in the presence of acidosis. This results in a down­ acetylation for proliferation and metastasis. In particular, cancer cells
regulation of ACC2 expression. In this situation, FAO and FAS occur need lipid metabolism to provide energy and a large number of mem­
concomitantly. This alteration allows tumor cells to proliferate in an brane structures to complete their own life activities, and regulate genes
acidic environment. [145] that play a role in tumorigenesis and development through histone
Alterations starting with lipid synthesis, lipolysis and acetyl-CoA and acetylation.
histone acetylation can have an impact among this complex relationship
network. The specific positive or negative feedback regulation in this
relationship network needs to be further investigated.

7
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