The role of acetylation and deacetylation in cancer metabolism

Abstract

As a hallmark of cancer, metabolic reprogramming adjusts macromolecular synthesis, energy metabolism and redox homeostasis processes to adapt to and promote the complex biological processes of abnormal growth and proliferation. The complexity of metabolic reprogramming lies in its precise regulation by multiple levels and factors, including the interplay of multiple signalling pathways, precise regulation of transcription factors and dynamic adjustments in metabolic enzyme activity. In this complex regulatory network, acetylation and deacetylation, which are important post-translational modifications, regulate key molecules and processes related to metabolic reprogramming by affecting protein function and stability. Dysregulation of acetylation and deacetylation may alter cancer cell metabolic patterns by affecting signalling pathways, transcription factors and metabolic enzyme activity related to metabolic reprogramming, increasing the susceptibility to rapid proliferation and survival. In this review, we focus on discussing how acetylation and deacetylation regulate cancer metabolism, thereby highlighting the central role of these post-translational modifications in metabolic reprogramming, and hoping to provide strong support for the development of novel cancer treatment strategies. KEY POINTS: Protein acetylation and deacetylation are key regulators of metabolic reprogramming in tumour cells. These modifications influence signalling pathways critical for tumour metabolism. They modulate the activity of transcription factors that drive gene expression changes. Metabolic enzymes are also affected, altering cellular metabolism to support tumour growth.

Keywords: acetylation; cancer; deacetylation; metabolic reprogramming.

FIGURE 1

Modulation of the reversible process of lysine acetylation. (A) Schematic diagram of the reversible process of histone modifications created by Biorender. In the green circle, Ac represents the acetyl group. In the purple circle, CoA represents coenzyme A. (B) Classification of acetyltransferases. The remaining KATs, which are classified as ‘other’, exhibit relatively minor dissimilarities among themselves, and research on this particular aspect has been relatively scarce. (C) Classification of deacetylases. Lysine deacetylases (KDACs) can be classified into two primary classes: classical HDACs, which rely on Zn2+ for their activity, and sirtuin deacetylases, which are dependent on NAD+. Within these broader categories, KDACs can be further subcategorised into Class I, Class IIa, Class IIb, Class III and Class IV. CBP, CREB‐binding protein; GCN5, general control of amino acid synthesis protein 5; GNAT, GCN5‐related N‐acetyltransferases; HATs, histone acetyltransferases; HBO1, histone acetyltransferase binding to ORC1; HDACs, histone deacetylases; KATs, lysine acetyltransferases; KDACs, lysine deacetylases; MOF, males absent on the first; MORF, monocytic leukemic zinc finger‐related factor; MOZ, monocytic leukaemia zinc finger protein; MYST, MOZ/Ybf2 (Sas3)/Sas2/Tip60; NAD, nicotinamide adenine dinucleotide; PCAF, p300/CBP‐associated factor; RNAPII, RNA polymerase II; SIRT, sirtuin; Tip60, 60 kDa tat‐interactive protein.

FIGURE 2

Regulation of signalling pathways and transcription factors related to cancer metabolism through acetylation and deacetylation. Red text indicates the positive regulatory relationship of acetyltransferases and deacetylase on protein activity or expression levels. Blue text indicates the negative regulatory relationship of acetyltransferases and deacetylase on protein activity or expression levels. AKT, serine/threonine kinase B; AMPK, AMP‐activated protein kinase; ARD‐1, antisense arrest‐defective 1 protein; c‐myc, cellular myelocytomatosis oncogene; ERK1/2, extracellular signal‐regulated kinase 1/2; FOXOs, forkhead box class O proteins; GluR, glutamate receptors; GSK3β, glycogen synthase kinase‐3 beta; HIF‐1α, hypoxia inducible factor‐1α; JAK, Janus kinase; LKB1, liver kinase B1; Loxl3, LOX‐like 3; MDM2, mouse double minute 2 homolog; MEK1/2, MAPK/ERK kinase1/2; MTA, metastasis‐associated protein; mTORC, mechanistic target of rapamycin complex; Naa20, N‐α‐acetyltransferase 20; NAT10, N‐acetyltransferase 10; NRF2, nuclear factor erythroid‐2‐related factor‐2; PBRM1, polybromo‐1; PDK1, 3‐phosphoinositide‐dependent protein kinase 1; PI3K, phosphatidylinositol 3‐kinase; PIP2, phosphatidylinositol 4,5‐bisphosphate; PIP3, phosphatidylinositol 3,4,5‐trisphosphate; PTEN, phosphatase and tensin homolog; Ras, rat sarcoma; ROS, reactive oxygen species; RTK1 receptor tyrosine kinase; SREBP, sterol‐regulatory element binding proteins; STAT3, signal transducer and activator of transcription 3; TSC1/2, tuberous sclerosis complex1/2.

FIGURE 3

Summary of the mechanisms of FoxO1/3a acetylation in cancer.

FIGURE 4

In the regulation of cancer metabolism, metabolic enzymes involved in glucose, fatty acid and amino acid metabolic pathways are finely regulated by acetylation and deacetylation processes, thereby achieving tight control of cancer cell metabolic pathways. Red text indicates the positive regulatory relationship of acetyltransferases and deacetylase on protein activity or expression levels. Blue text indicates the negative regulatory relationship of acetyltransferases and deacetylase on protein activity or expression levels. 1,3‐BPG, 1,3‐biphosphoglycerate; 2‐PG, 2‐phosphoglycerate; 3‐PG, 3‐phosphoglycerate; 6PGD, 6‐phosphogluconate dehydrogenase; ACAT, acetyl‐CoA acetyltransferase; ACC, acetyl‐CoA carboxylase; ACLY, ATP citrate lyase; ACO, cis‐aconitase; ASCT2, alanine‐serine‐cystenine transporter2; Asp, aspartate; CPT, carnitine palmitoyltransferase; CS, citrate synthase; DHAP, dihydroxyacetone phosphate; DLAT, dihydrolipoamide S‐acetyltransferase; ENO, enolase; EZHIP, enhancer of zeste homologs inhibitory protein; F‐1,6‐BP, fructose‐1,6‐bisphosphate; F‐6‐P, fructose‐6‐phosphate; FA‐CoA, fatty acyl‐CoA; FACS, fatty acyl‐CoA synthetase; FASN, fatty acid synthase; FH, fumarase; G‐6‐P, glucose‐6‐phosphate; G6PD, glucose 6‐phosphate dehydrogenase; GAP, glyceraldehyde‐3‐phosphate; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; GDH, glutamate dehydrogenase; GLS, glutaminase; GLUT, glucose transporter; GOT, glutamate: oxaloacetate transaminase; HGDILnc1, hypoxia and glucose deprivation‐induced lncRNA; HK, hexokinase; HMGCR, HMG‐CoA reductase; HMGCS, HMG‐CoA synthase; IDH, isocitrate dehydrogenase; JOSD2, Josephin domain containing 2; LDH, lactate dehydrogenase; LOXL2, lysyl oxidase‐like 2; MD, malate dehydrogenase; OAA, oxaloacetate; OGDH, α‐ketoglutarate dehydrogenase; PDH, pyruvate dehydrogenase; PEP, phosphoenolpyruvate; PFK‐1, phosphofructokinase‐1; PGAM, phosphoglycerate mutase; PGK, phosphoglycerate kinase; PHGDH, 3‐phosphoglycerate dehydrogenase; PHI, phosphohexose isomerase; PK, pyruvate kinase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SCS, succinyl‐CoA synthetase; SDH, succinate dehydrogenase; SHMT, serine transhydroxymethylase; TIM, triose phosphate isomerase; TSP50, testes‐specific protease 50.