{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:02:40Z","timestamp":1784782960045,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Epigenetic alterations promote colorectal cancer (CRC) development, plasticity, and drug resistance. Agents have been developed to target epigenetic modifiers; however, they demonstrate limited clinical efficacy. This outcome is the result of the complex interplay within the epigenome, as well as that of the molecular circuits linking these epigenetic vulnerabilities with genetic mutations, oncogenic pathways, and activation of transcription factors. Therefore, current evidence suggests these agents should be assessed in combination with regimens including additional epigenetic drugs, immune checkpoint inhibitors, monoclonal antibodies, and chemotherapeutic drugs. Herein, we highlight recent advances towards epigenome-centered treatment strategies in CRC. We also prioritize potential efforts of epigenetic-associated therapeutic modalities, which should be further developed following integration of respective biomarkers and as tools of therapeutic reprogramming in context-dependent cellular states.<\/jats:p>","DOI":"10.3390\/ijms27146486","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:17:52Z","timestamp":1784647072000},"page":"6486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the Epigenome in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4332-6409","authenticated-orcid":false,"given":"Antonios N.","family":"Gargalionis","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-745X","authenticated-orcid":false,"given":"Kostas A.","family":"Papavassiliou","sequence":"additional","affiliation":[{"name":"First University Department of Respiratory Medicine, \u2018Sotiria\u2019 Chest Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5803-4527","authenticated-orcid":false,"given":"Athanasios G.","family":"Papavassiliou","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1136\/gutjnl-2022-327736","article-title":"Global burden of colorectal cancer in 2020 and 2040: Incidence and mortality estimates from GLOBOCAN","volume":"72","author":"Morgan","year":"2023","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41419-026-08720-2","article-title":"Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression","volume":"17","author":"Li","year":"2026","journal-title":"Cell Death Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100881","DOI":"10.1016\/j.xgen.2025.100881","article-title":"Phenotypic heterogeneity and plasticity in colorectal cancer metastasis","volume":"5","author":"Ogden","year":"2025","journal-title":"Cell Genom."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1053\/j.gastro.2025.07.003","article-title":"Chemical Perturbations Impacting Histone Acetylation Govern Colorectal Cancer Differentiation","volume":"170","author":"Likasitwatanakul","year":"2026","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"131","DOI":"10.5217\/ir.2023.00115","article-title":"Pathogenesis and biomarkers of colorectal cancer by epigenetic alteration","volume":"22","author":"Oh","year":"2024","journal-title":"Intest. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yang, S., Huang, Y., and Zhao, Q. (2022). Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.878740"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13148-025-01844-w","article-title":"Epigenetic marvels: Exploring the landscape of colorectal cancer treatment through cutting-edge epigenetic-based drug strategies","volume":"17","author":"Tahghighi","year":"2025","journal-title":"Clin. Epigenet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103062","DOI":"10.1016\/j.ctrv.2025.103062","article-title":"Harnessing epigenetics: Genome-wide DNA methylation assay for colorectal cancer therapy","volume":"143","author":"Ishioka","year":"2026","journal-title":"Cancer Treat. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s13148-025-01940-x","article-title":"Genome-wide DNA methylation profiles of colorectal tumors in Lynch syndrome and familial adenomatous polyposis","volume":"17","author":"Kauppinen","year":"2025","journal-title":"Clin. Epigenet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13148-025-01817-z","article-title":"DNA methylation profiling at base-pair resolution reveals unique epigenetic features of early-onset colorectal cancer in underrepresented populations","volume":"17","author":"Li","year":"2025","journal-title":"Clin. Epigenet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45283","DOI":"10.1038\/s41598-025-28656-5","article-title":"Dynamic DNA methylation changes during colorectal oncogenesis with insights from adenoma stages","volume":"15","author":"Overs","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/ng1834","article-title":"CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer","volume":"38","author":"Weisenberger","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/modpathol.3800982","article-title":"CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci","volume":"21","author":"Kawasaki","year":"2008","journal-title":"Mod. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"112905","DOI":"10.1016\/j.isci.2025.112905","article-title":"BRAF(V600E) maintains the CpG island methylator phenotype, and DNA methylation of PRC2 targets genes in colon cancer","volume":"28","author":"Bugter","year":"2025","journal-title":"iScience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1186\/s13059-023-03108-3","article-title":"Cooperation of MLL1 and Jun in controlling H3K4me3 on enhancers in colorectal cancer","volume":"24","author":"Lin","year":"2023","journal-title":"Genome Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5166","DOI":"10.1158\/1078-0432.CCR-24-1166","article-title":"Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer","volume":"30","author":"Lee","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Dreier, M.R., Walia, J., and de la Serna, I.L. (2024). Targeting SWI\/SNF Complexes in Cancer: Pharmacological Approaches and Implications. Epigenomes, 8.","DOI":"10.3390\/epigenomes8010007"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1158\/0008-5472.CAN-25-3231","article-title":"ARID1A Mediates SWI\/SNF-Independent Maintenance of Heterochromatin Architecture to Restrain Viral Mimicry and Immunogenicity in Colon Cancer","volume":"86","author":"Li","year":"2026","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"218679","DOI":"10.1016\/j.canlet.2026.218679","article-title":"Cellular plasticity and epigenetic instability in cancer: Mechanistic insights and functional dissection with CRISPR-based epigenome editing","volume":"656","author":"Fatima","year":"2026","journal-title":"Cancer Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.biocel.2010.03.018","article-title":"Colon carcinogenesis: Learning from NF-kappaB and AP-1","volume":"42","author":"Vaiopoulos","year":"2010","journal-title":"Int. J. Biochem Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Patnaik, S. (2019). Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00588"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1007\/s10637-013-9947-6","article-title":"A phase I\/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer","volume":"31","author":"McGregor","year":"2013","journal-title":"Investig. New Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.1039\/D5RA09034B","article-title":"HDAC inhibitors as anticancer drugs: Chemical diversity, clinical trials, challenges and perspectives","volume":"16","author":"Abdallah","year":"2026","journal-title":"RSC Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.2147\/OTT.S30773","article-title":"Profile of panobinostat and its potential for treatment in solid tumors: An update","volume":"6","author":"Anne","year":"2013","journal-title":"OncoTargets Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35326","DOI":"10.18632\/oncotarget.15108","article-title":"Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: A phase 2 consortium\/stand up 2 cancer study","volume":"8","author":"Azad","year":"2017","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.cell.2015.07.011","article-title":"Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses","volume":"162","author":"Chiappinelli","year":"2015","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/ahg.12528","article-title":"Histone modification: Biomarkers and potential therapies in colorectal cancer","volume":"87","author":"An","year":"2023","journal-title":"Ann. Hum. Genet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eadk4423","DOI":"10.1126\/sciadv.adk4423","article-title":"Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling","volume":"10","author":"Chomiak","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13148-023-01500-1","article-title":"Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas","volume":"15","author":"Tang","year":"2023","journal-title":"Clin. Epigenet."},{"key":"ref_31","first-page":"949","article-title":"Transcription factors and neoplasia: Vistas in novel drug design","volume":"8","author":"Karamouzis","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13148-023-01485-x","article-title":"A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer","volume":"15","author":"Baretti","year":"2023","journal-title":"Clin. Epigenet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.7150\/jca.44622","article-title":"HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment","volume":"11","author":"Kim","year":"2020","journal-title":"J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1186\/s12951-024-02936-0","article-title":"HDACi combination therapy with IDO1i remodels the tumor microenvironment and boosts antitumor efficacy in colorectal cancer with microsatellite stability","volume":"22","author":"Liang","year":"2024","journal-title":"J. Nanobiotechnology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1038\/s41416-023-02267-1","article-title":"Phase I\/II sequencing study of azacitidine, epacadostat, and pembrolizumab in advanced solid tumors","volume":"128","author":"Luke","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/s41591-024-02813-1","article-title":"Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS\/pMMR colorectal cancer: A randomized phase 2 trial","volume":"30","author":"Wang","year":"2024","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1186\/s12935-025-03992-8","article-title":"Epigenetic potentiation of 5-fluorouracil by HDAC inhibitor quisinostat enhances antitumor effects in colorectal cancer","volume":"25","author":"Kurter","year":"2025","journal-title":"Cancer Cell Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1158\/2159-8290.CD-23-0866","article-title":"Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers","volume":"14","author":"Loi","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/s41419-022-04745-5","article-title":"Activation of FXR and inhibition of EZH2 synergistically inhibit colorectal cancer through cooperatively accelerating FXR nuclear location and upregulating CDX2 expression","volume":"13","author":"Yu","year":"2022","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6486\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:22:42Z","timestamp":1784780562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":39,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146486"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146486","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]}}}