ROLE OF EPIGENETIC MODIFICATIONS IN TUMOR SUPPRESSOR GENE SILENCING AMONG PATIENTS WITH SPORADIC COLORECTAL CANCER: NARRATIVE REVIEW
DOI:
https://doi.org/10.71000/xghqe876Keywords:
Sporadic Colorectal Cancer, Tumor Suppressor Genes, Epigenetic Silencing, DNA Methylation, MicroRNA, , Narrative ReviewAbstract
Background: Sporadic colorectal cancer (CRC), which constitutes the majority of CRC cases, is primarily driven by acquired molecular changes rather than inherited mutations. Among these, epigenetic alterations—specifically the silencing of tumor suppressor genes—play a crucial role in colorectal tumorigenesis. Understanding these reversible and dynamic modifications offers significant potential for enhancing early detection, prognosis, and targeted therapy.
Objective: This narrative review aims to explore the role of epigenetic modifications in the silencing of tumor suppressor genes in patients with sporadic colorectal cancer, synthesizing current findings and identifying implications for clinical practice and future research.
Main Discussion Points: Key epigenetic mechanisms discussed include promoter hypermethylation of genes such as MLH1, MGMT, and CDKN2A; long-range epigenetic silencing across chromosomal regions; histone modification patterns contributing to chromatin inactivation; and microRNA suppression involved in early tumorigenesis. The review also highlights variability in study methodologies, population-specific differences, and gaps in longitudinal and functional research. Limitations related to sample size, design, and generalizability are critically analyzed.
Conclusion: Epigenetic silencing of tumor suppressor genes is a central event in sporadic CRC development, with clear implications for biomarker discovery and therapeutic targeting. While current evidence is promising, more standardized and mechanistically focused studies are needed to translate these findings into clinical applications and guidelines.
References
Ghate NB, Kim S, Spiller E, Kim S, Shin Y, Rhie SK, et al. VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer. Mol Oncol. 2021;15(10):2801-17.
Ren Y, Qian Y, Ai L, Xie Y, Gao Y, Zhuang Z, et al. TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity. Nat Commun. 2021;12(1):5405.
Islam M, Yang Y, Simmons AJ, Shah VM, Musale KP, Xu Y, et al. Temporal recording of mammalian development and precancer. Nature. 2024;634(8036):1187-95.
Xie J, Wang S. Small Interfering RNA in Colorectal Cancer Liver Metastasis Therapy. Technol Cancer Res Treat. 2022;21:15330338221103318.
Liu Z, Tao J, Zhu Y, Li D, Teng L. Silencing CXCR6 promotes epithelial-mesenchymal transition and invasion in colorectal cancer by activating the VEGFA/PI3K/AKT/mTOR pathway. Int Immunopharmacol. 2024;143(Pt 3):113529.
Li S, Li X, Xue W, Zhang L, Yang LZ, Cao SM, et al. Screening for functional circular RNAs using the CRISPR-Cas13 system. Nat Methods. 2021;18(1):51-9.
Jebelli A, Baradaran B, Mosafer J, Baghbanzadeh A, Mokhtarzadeh A, Tayebi L. Recent developments in targeting genes and pathways by RNAi-based approaches in colorectal cancer. Med Res Rev. 2021;41(1):395-434.
Khorshid Sokhangouy S, Alizadeh F, Lotfi M, Sharif S, Ashouri A, Yoosefi Y, et al. Recent advances in CRISPR-Cas systems for colorectal cancer research and therapeutics. Expert Rev Mol Diagn. 2024;24(8):677-702.
Jian W, Zhang L. POLE2 silencing inhibits the progression of colorectal carcinoma cells via wnt signaling axis. Cancer Biol Ther. 2024;25(1):2392339.
Yan HHN, Siu HC, Ho SL, Yue SSK, Gao Y, Tsui WY, et al. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles. Gut. 2020;69(12):2165-79.
Zhang KL, Zhu WW, Wang SH, Gao C, Pan JJ, Du ZG, et al. Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer. Theranostics. 2021;11(13):6560-72.
Ma SC, Zhang JQ, Yan TH, Miao MX, Cao YM, Cao YB, et al. Novel strategies to reverse chemoresistance in colorectal cancer. Cancer Med. 2023;12(10):11073-96.
Guo M, Zhang X. LncRNA MSTO2P promotes colorectal cancer progression through epigenetically silencing CDKN1A mediated by EZH2. World J Surg Oncol. 2022;20(1):95.
Fakhr E, Zare F, Azadmanesh K, Teimoori-Toolabi L. LEF1 silencing sensitizes colorectal cancer cells to oxaliplatin, 5-FU, and irinotecan. Biomed Pharmacother. 2021;143:112091.
Wang YY, Lin JF, Wu WW, Fu Z, Cao F, Chen YX, et al. Inhibition of MBTPS1 enhances antitumor immunity and potentiates anti-PD-1 immunotherapy. Nat Commun. 2025;16(1):4047.
Borrelli C, Roberts M, Eletto D, Hussherr MD, Fazilaty H, Valenta T, et al. In vivo interaction screening reveals liver-derived constraints to metastasis. Nature. 2024;632(8024):411-8.
Boughanem H, Pilo J, García-Flores LA, Arranz I, Ramos-Fernandez M, Ortega-Castan M, et al. Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance. J Transl Med. 2024;22(1):509.
Yu C, Luo D, Yu J, Zhang M, Zheng X, Xu G, et al. Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer. Oncogene. 2022;41(2):191-203.
Relier S, Ripoll J, Guillorit H, Amalric A, Achour C, Boissière F, et al. FTO-mediated cytoplasmic m(6)A(m) demethylation adjusts stem-like properties in colorectal cancer cell. Nat Commun. 2021;12(1):1716.
Yuan Z, Yu X, Chen W, Chen D, Cai J, Jiang Y, et al. Epigenetic silencing and tumor suppressor gene of HAND2 by targeting ERK signaling in colorectal cancer. Cell Commun Signal. 2022;20(1):111.
Zhou Y, Yang Z, Zhang H, Li H, Zhang M, Wang H, et al. DNMT3A facilitates colorectal cancer progression via regulating DAB2IP mediated MEK/ERK activation. Biochim Biophys Acta Mol Basis Dis. 2022;1868(4):166353.
Hu Y, Liu L, Jiang Q, Fang W, Chen Y, Hong Y, et al. CRISPR/Cas9: a powerful tool in colorectal cancer research. J Exp Clin Cancer Res. 2023;42(1):308.
Gupta MK, Gouda G, Moazzam-Jazi M, Vadde R, Nagaraju GP, El-Rayes BF. CRISPR/Cas9-directed epigenetic editing in colorectal cancer. Biochim Biophys Acta Rev Cancer. 2025;1880(3):189338.
Zhong C, Jiang WJ, Yao Y, Li Z, Li Y, Wang S, et al. CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer. Nat Commun. 2024;15(1):5502.
Liu X, Liu Y, Liu Z, Lin C, Meng F, Xu L, et al. CircMYH9 drives colorectal cancer growth by regulating serine metabolism and redox homeostasis in a p53-dependent manner. Mol Cancer. 2021;20(1):114.
Sun G, Zhao S, Fan Z, Wang Y, Liu H, Cao H, et al. CHSY1 promotes CD8(+) T cell exhaustion through activation of succinate metabolism pathway leading to colorectal cancer liver metastasis based on CRISPR/Cas9 screening. J Exp Clin Cancer Res. 2023;42(1):248.
Meng H, Nan M, Li Y, Ding Y, Yin Y, Zhang M. Application of CRISPR-Cas9 gene editing technology in basic research, diagnosis and treatment of colon cancer. Front Endocrinol (Lausanne). 2023;14:1148412.
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Copyright (c) 2025 Irfan Ishaque, Hafsa Hameed Thakur, Noor Us Sabah Ahmed , Attiq Ullah , Amna Noor , Muhammad Anser Akram (Author)

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