Advances of therapy targeting epigenetic regulation for cancer

doi:10.16139/j.1007-9610.2026.01.14

Abstract

Abstract:

The article reviewed the progress in cancer therapy targeting epigenetic regulation, introduced the basic concepts of epigenetics and its role in tumorigenesis and development. Epigenetics refers to heritable changes in gene expression that occur without alterations in the DNA sequence. It precisely controls the temporal-spatial-specific expression of genes through dynamic and reversible DNA and histone modification, and non-coding RNA-mediated regulatory networks. The article discussed the mechanisms of epigenetic regulatory and chromatin remodeling, and described the abnormal manifestations of these mechanisms in tumors. Furthermore, the article reviewed the progress in drug development targeting epigenetic regulation. Finally, the article discussed the combined application of targeted epigenetic therapy with other conventional treatment modalities, and proposed future research directions and challenges.

Key words: Epigenetic regulation, Cancer therapy, Targeted therapy, Chromatin spatial structure, Epigenetic drug

CLC Number:

WEI Lan, SANG Qingqing, LIU Bingya. Advances of therapy targeting epigenetic regulation for cancer[J]. Journal of Surgery Concepts & Practice, 2026, 31(01): 80-87.

Figures/Tables 4

References 50

[1]	ILANGO S, PAITAL B, JAYACHANDRAN P, et al. Epigenetic alterations in cancer[J]. Front Biosci (Landmark Ed), 2020, 25(6):1058-1109. doi: 10.2741/4847 pmid: 32114424
[2]	RAMAIAH M J, TANGUTUR A D, MANYAM R R. Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy[J]. Life Sci, 2021, 277:119504. doi: 10.1016/j.lfs.2021.119504 URL
[3]	BIRD A. DNA methylation patterns and epigenetic memory[J]. Genes Dev, 2002, 16(1):6-21. doi: 10.1101/gad.947102 URL
[4]	张丽丽, 吴建新. DNA甲基化——肿瘤产生的一种表观遗传学机制[J]. 遗传, 2006, 28(7):880-885.
	ZHANG L L, WU J X. DNA methylation: an epigenetic mechanism in tumorigenesis[J] Hereditas, 2006, 28(7):880-885.
[5]	WU X, ZHANG Y. TET-mediated active DNA demethylation: mechanism, function and beyond[J]. Nat Rev Genet, 2017, 18(9):517-534. doi: 10.1038/nrg.2017.33 pmid: 28555658
[6]	WANG D, WU W, CALLEN E, et al. Active DNA demethylation promotes cell fate specification and the DNA damage response[J]. Science, 2022, 378(6623):983-989. doi: 10.1126/science.add9838 pmid: 36454826
[7]	ALLIS C D, JENUWEIN T. The molecular hallmarks of epigenetic control[J]. Nat Rev Genet, 2016, 17(8):487-500. doi: 10.1038/nrg.2016.59 pmid: 27346641
[8]	SANKAR A, MOHAMMAD F, SUNDARAMURTHY A K, et al. Histone editing elucidates the functional roles of H3K27 methylation and acetylation in mammals[J]. Nat Genet, 2022, 54(6):754-760. doi: 10.1038/s41588-022-01091-2 pmid: 35668298
[9]	ZOU Y, BAI X H, KONG L C, et al. Involvement of histone lysine crotonylation in the regulation of nerve-injury-induced neuropathic pain[J]. Front Immunol, 2022, 13:885685. doi: 10.3389/fimmu.2022.885685 URL
[10]	MEISTER S, KELLNER I, BEYER S, et al. Epigenetic changes occur in placentas of spontaneous and recurrent miscarriages[J]. J Reprod Immunol, 2022, 149:103466. doi: 10.1016/j.jri.2021.103466 URL
[11]	CHEN Q, YANG B, LIU X, et al. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents[J]. Theranostics, 2022, 12(11):4935-4948. doi: 10.7150/thno.73223 pmid: 35836809
[12]	VERMA A, SINGH A, SINGH M P, et al. EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis[J]. Nat Commun, 2022, 13(1):7344. doi: 10.1038/s41467-022-35059-x pmid: 36446780
[13]	BELTON J M, MCCORD R P, GIBCUS J H, et al. Hi-C: a comprehensive technique to capture the conformation of genomes[J]. Methods, 2012, 58(3):268-276. doi: 10.1016/j.ymeth.2012.05.001 URL
[14]	MENDEZ-DORANTES C, BURNS K H. LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities[J]. Genes Dev, 2023, 37(21-24):948-967. doi: 10.1101/gad.351051.123 URL
[15]	RECAGNI M, BIDZINSKA J, ZAFFARONI N, et al. The role of alternative lengthening of telomeres mechanism in cancer: translational and therapeutic implications[J]. Cancers (Basel), 2020, 12(4):949. doi: 10.3390/cancers12040949 URL
[16]	DE CARVALHO D D, SHARMA S, YOU J S, et al. DNA methylation screening identifies driver epigenetic events of cancer cell survival[J]. Cancer Cell, 2012, 21(5):655-667. doi: 10.1016/j.ccr.2012.03.045 pmid: 22624715
[17]	ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes[J]. Nature, 2020, 578(7793):82-93. doi: 10.1038/s41586-020-1969-6
[18]	WU S, ZHANG J, CHEN S, et al. Low NDRG2, regulated by the MYC/MIZ-1 complex and methylation, predicts poor outcomes in DLBCL patients[J]. Ann Hematol, 2024, 103(8):2877-2892. doi: 10.1007/s00277-024-05829-2 pmid: 38842567
[19]	SKOWRONSKI K, DUBEY S, RODENHISER D, et al. Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells[J]. Epigenetics, 2010, 5(6):547-556. pmid: 20543577
[20]	BOUVET D, BODO S, MUNIER A, et al. Methylation to-lerance-based functional assay to assess variants of unknown significance in the MLH1 and MSH2 genes and identify patients with lynch syndrome[J]. Gastroentero-logy, 2019, 157(2):421-431.
[21]	GHALKHANI E, AKBARI M T, IZADI P, et al. Assessment of DAPK1 and CAVIN3 gene promoter methylation in breast invasive ductal carcinoma and metastasis[J]. Cell J, 2021, 23(4):397-405.
[22]	BURR M L, SPARBIER C E, CHAN K L, et al. An evolutionarily conserved function of polycomb silences the MHC class Ⅰ antigen presentation pathway and enables immune evasion in cancer[J]. Cancer Cell, 2019, 36(4):385-401.e388. doi: 10.1016/j.ccell.2019.08.008 URL
[23]	LIU J, LIANG L, HUANG S, et al. Aberrant differential expression of EZH2 and H3K27me3 in extranodal NK/T-cell lymphoma, nasal type, is associated with disease progression and prognosis[J]. Hum Pathol, 2019, 83:166-176. doi: S0046-8177(18)30351-4 pmid: 30218753
[24]	MARSCHALEK R. MLL leukemia and future treatment strategies[J]. Arch Pharm (Weinheim), 2015, 348(4):221-228. doi: 10.1002/ardp.v348.4 URL
[25]	BERGER L, KOLBEN T, MEISTER S, et al. Expression of H3K4me3 and H3K9ac in breast cancer[J]. J Cancer Res Clin Oncol, 2020, 146(8):2017-2027. doi: 10.1007/s00432-020-03265-z pmid: 32468423
[26]	DOU R, HAN L, YANG C, et al. Upregulation of LINC00501 by H3K27 acetylation facilitates gastric cancer metastasis through activating epithelial-mesenchymal transition and angiogenesis[J]. Clin Transl Med, 2023, 13(10):e1432. doi: 10.1002/ctm2.1432 pmid: 37867401
[27]	FLAVAHAN W A, GASKELL E, BERNSTEIN B E. Epigenetic plasticity and the hallmarks of cancer[J]. Science, 2017, 357(6348):eaal2380. doi: 10.1126/science.aal2380 URL
[28]	TABERLAY P C, ACHINGER-KAWECKA J, LUN A T, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations[J]. Genome Res, 2016, 26(6):719-731. doi: 10.1101/gr.201517.115 pmid: 27053337
[29]	SEELAN R S, MUKHOPADHYAY P, PISANO M M, et al. Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression[J]. Drug Metab Rev, 2018, 50(2):193-207. doi: 10.1080/03602532.2018.1437446 pmid: 29455551
[30]	HACKANSON B, DASKALAKIS M. Decitabine[J]. Recent Results Cancer Res, 2014, 201:269-297. doi: 10.1007/978-3-642-54490-3_18 pmid: 24756800
[31]	GOLDFINGER M, MANTZARIS I, SHASTRI A, et al. A weekly low-dose regimen of decitabine and venetoclax is efficacious and less myelotoxic in a racially diverse cohort[J]. Blood, 2024, 144(22):2360-2363. doi: 10.1182/blood.2024025834 pmid: 39316768
[32]	ŠIMONIČOVÁ K, JANOTKA Ľ, KAVCOVÁ H, et al. Different mechanisms of drug resistance to hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukemia[J]. Drug Resist Updat, 2022, 61:100805. doi: 10.1016/j.drup.2022.100805 URL
[33]	GARCIA-MANERO G, DÖHNER H, WEI A H, et al. Oral azacitidine (CC-486) for the treatment of myeloid malignancies[J]. Clin Lymphoma Myeloma Leuk, 2022, 22(4):236-250. doi: 10.1016/j.clml.2021.09.021 URL
[34]	WONG K K. DNMT1: a key drug target in triple-negative breast cancer[J]. Semin Cancer Biol, 2021, 72:198-213. doi: 10.1016/j.semcancer.2020.05.010 pmid: 32461152
[35]	LI X, SONG Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy[J]. J Hematol Oncol, 2020, 13(1):50. doi: 10.1186/s13045-020-00885-3
[36]	PARVEEN R, HARIHAR D, CHATTERJI B P. Recent histone deacetylase inhibitors in cancer therapy[J]. Cancer, 2023, 129(21):3372-3380. doi: 10.1002/cncr.34974 pmid: 37560925
[37]	BOSE P, DAI Y, GRANT S. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights[J]. Pharmacol Ther, 2014, 143(3):323-336. doi: 10.1016/j.pharmthera.2014.04.004 URL
[38]	CARREIRAS M D C, MARCO-CONTELLES J. Hydrazides as inhibitors of histone deacetylases[J]. J Med Chem, 2024, 67(16):13512-13533. doi: 10.1021/acs.jmedchem.4c00541 pmid: 39092855
[39]	LI D, PENG X, HU Z, et al. Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: current progress and novel strategies[J]. Eur J Med Chem, 2024, 264:115982. doi: 10.1016/j.ejmech.2023.115982 URL
[40]	MORSCHHAUSER F, TILLY H, CHAIDOS A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial[J]. Lancet Oncol, 2020, 21(11):1433-1442. doi: 10.1016/S1470-2045(20)30441-1 pmid: 33035457
[41]	MARCOS-VILLAR L, NIETO A. The DOT1L inhibitor pinometostat decreases the host-response against infections: considerations about its use in human therapy[J]. Sci Rep, 2019, 9(1):16862. doi: 10.1038/s41598-019-53239-6
[42]	SORAGNI E, CHOU C J, RUSCHE J R, et al. Mechanism of action of 2-aminobenzamide HDAC inhibitors in reversing gene silencing in Friedreich's ataxia[J]. Front Neurol, 2015, 6:44. doi: 10.3389/fneur.2015.00044 pmid: 25798128
[43]	MAES T, MASCARÓ C, TIRAPU I, et al. ORY-1001, a potent and selective covalent KDM1A inhibitor, for the treatment of acute leukemia[J]. Cancer Cell, 2018, 33(3):495-511.e12. doi: S1535-6108(18)30023-0 pmid: 29502954
[44]	DALPATRAJ N, NAIK A, THAKUR N. GSK-J4: An H3K27 histone demethylase inhibitor, as a potential anti-cancer agent[J]. Int J Cancer, 2023, 153(6):1130-1138. doi: 10.1002/ijc.34559 pmid: 37165737
[45]	CAI R, LV R, SHI X, et al. CRISPR/dCas9 tools: epigenetic mechanism and application in gene transcriptional regulation[J]. Int J Mol Sci, 2023, 24(19):14865. doi: 10.3390/ijms241914865 URL
[46]	WANG Q, MA C, MAO H, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates the ZNF334 gene to inhibit the growth of colorectal cancer[J]. Int J Biol Macromol, 2024, 277(Pt 4):134580. doi: 10.1016/j.ijbiomac.2024.134580 URL
[47]	YU J, CHEN M, SANG Q, et al. Super-enhancer activates master transcription factor NR3C1 expression and promotes 5-FU resistance in gastric cancer[J]. Adv Sci (Weinh), 2025, 12(7):e2409050.
[48]	RAI S K, MARVERTI G, GUNNAM A, et al. Dabrafenib-panobinostat salt: improving the dissolution rate and inhibition of BRAF melanoma cells[J]. ACS Omega, 2023, 8(20):18255-18265. doi: 10.1021/acsomega.3c01881 pmid: 37251170
[49]	LI F, YU J, PAN T, et al. BPTF drives gastric cancer resistance to EGFR inhibitor by epigenetically regulating the C-MYC/PLCG1/Perk axis[J]. Adv Sci (Weinh), 2023, 10(34):e2303091.
[50]	SURAWEERA A, O'BYRNE K J, RICHARD D J. Epigenetic drugs in cancer therapy[J]. Cancer Metastasis Rev, 2025, 44(1):37. doi: 10.1007/s10555-025-10253-7

Medication	Target	Indications	Side effects
5-AZA、decitabine	DNMTs	MDS、AML、CMML	Bone marrow suppression, pancytopenia
Iadademstat	LSD1	AML、Small-cell lung cancer	No studies have demonstrated
GSK-J4	KDM6A	Neuroblastoma Glioblastoma
Tazemetostat	H3K27me3	Follicular lymphoma and epithelioid sarcoma
Pinometostat	H3K79me	MLL、AML
Vorinostat、Romidepsin、Belinostat	HDACs	CTCL、MM	Drug resistance