IJGPNInternational Journal of General Practice Nursing2981-94152981-9423Bio-Byword Scientific Publishing Pty. Ltd.10.26689/ijgpn.v3iSpecial.13954ArticleEpigenetic Regulatory Mechanisms of ZNF304 in Colorectal Cancer and Its Role in Migration and Invasionhttps://artdesignp.com/journal/IJGPN/3/0/10.26689/ijgpn.v3iSpecial.13954ZhengTing2025302025-12-31Colorectal cancer is one of the leading causes of cancer-related deaths worldwide, and its development involves complex genetic and epigenetic mechanisms. Epigenetic regulation, especially DNA methylation, plays a crucial role in tumorigenesis, progression, and metastasis. Epithelial-mesenchymal transition (EMT) is an important process promoting tumor cell invasion and metastasis, and epigenetic regulators such as TRIM28 and ZNF304 play key roles in this process. TRIM28 can regulate the expression of EMT-related genes by activating the TGF-β signaling pathway and histone modification; ZNF304, as a member of the C2H2 zinc finger transcription factor family, is closely related to cell survival, migration, and metastasis in various tumors. This review summarizes the epigenetic regulatory mechanisms of TRIM28 and ZNF304 in colorectal cancer, exploring their roles in the EMT process and tumor migration and invasion, providing new insights for the study of colorectal cancer metastasis mechanisms and targeted therapy.

Wild CP, 2019, The Global Cancer Burden: Necessity is the Mother of Prevention. Nat Rev Cancer, 19(3): 123–124.

Zheng R, Sun K, Zhang S, et al., 2023, Analysis of the Prevalence of Malignant Tumors in China in 2015. Chinese Journal of Oncology, 45(3): 9.

Brenner H, Kloor M, Pox CP, 2013, Colorectal Cancer. Lancet, 383(9927): 1490–1502.

Martin C, Zhang Y, 2007, Mechanisms of Epigenetic Inheritance. Curr Opin Cell Biol, 19(3): 266–272.

Probst AV, Dunleavy E, Almouzni G, 2009, Epigenetic Inheritance During the Cell Cycle. Nat Rev Mol Cell Biol, 10(3): 192–206.

Nieto MA, Huang RY-J, Jackson RA, et al., 2016, EMT: 2016. Cell, 166(1): 21–45.

Javaid S, Zhang J, Anderssen E, et al., 2013, Dynamic Chromatin Modification Sustains Epithelial-Mesenchymal Transition Following Inducible Expression of Snail-1. Cell Rep, 5(6): 1679–1689.

Thiery JP, Acloque H, Huang RYJ, et al., 2009, Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 139(5): 871–890.

Kalluri R, Weinberg RA, 2009, The Basics of Epithelial-Mesenchymal Transition. J Clin Invest, 119(6): 1420–1428.

Dongre A, Weinberg RA, 2019, New Insights into the Mechanisms of Epithelial-Mesenchymal Transition and Implications for Cancer. Nat Rev Mol Cell Biol, 20(2): 69–84.

Ye X, Tam WL, Shibue T, et al., 2015, Distinct EMT Programs Control Normal Mammary Stem Cells and Tumour-Initiating Cells. Nature, 525(7568): 256–260.

Lamouille S, Xu J, Derynck R, 2014, Molecular Mechanisms of Epithelial-Mesenchymal Transition. Nat Rev Mol Cell Biol, 15(3): 178–196.

Lindner P, Paul S, Eckstein M, et al., 2020, EMT Transcription Factor ZEB1 Alters the Epigenetic Landscape of Colorectal Cancer Cells. Cell Death Dis, 11(2): 147.

Sun L, Fang J, 2016, Epigenetic Regulation of Epithelial-Mesenchymal Transition. Cell Mol Life Sci, 73(23): 4493–4515.

Sánchez-Tilló E, Siles L, de Barrios O, et al., 2011, Expanding Roles of ZEB Factors in Tumorigenesis and Tumor Progression. Am J Cancer Res, 1(7): 897–912.

Zhang P, Sun Y, Ma L, 2015, ZEB1: At the Crossroads of Epithelial-Mesenchymal Transition, Metastasis and Therapy Resistance. Cell Cycle, 14(4): 481–487.

Krebs AM, Mitschke J, Lasierra Losada M, et al., 2017, The EMT-Activator Zeb1 is a Key Factor for Cell Plasticity and promotes Metastasis in Pancreatic Cancer. Nat Cell Biol, 19(5): 518–529.

Karihtala P, Auvinen P, Kauppila S, et al., 2013, Vimentin, zeb1 and Sip1 are Up-Regulated in Triple-Negative and Basal-Like Breast Cancers: Association with an Aggressive Tumour Phenotype. Breast Cancer Res Treat, 138(1): 81–90.

Liu Y, Lu X, Huang L, et al., 2015, Erratum: Different Thresholds of ZEB1 are Required for Ras-Mediated Tumour Initiation and Metastasis. Nat Commun, 6: 6699.

Huang F, Shi Q, Li Y, et al., 2018, HER2/EGFR-AKT Signaling Switches TGFβ from Inhibiting Cell Proliferation to Promoting Cell Migration in Breast Cancer. Cancer Res, 78(21): 6073–6085.

Gonzalez DM, Medici D, 2014, Signaling Mechanisms of the Epithelial-Mesenchymal Transition. Sci Signal, 7(344): re8.

Moustakas A, Heldin C-H, 2005, Non-Smad TGF-Beta Signals. J Cell Sci, 118(Pt 16): 3573–3584.

Chen W, Ten Dijke P, 2016, Immunoregulation by Members of the TGFβ Superfamily. Nat Rev Immunol, 16(12): 723–740.

Han Y, Liu Q, Hou J, et al., 2018, Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression. Cell, 173(3): 634–648.

Lee H-J, 2018, The Role of Tripartite Motif Family Proteins in TGF-β Signaling Pathway and Cancer. J Cancer Prev, 23(4): 162–169.

Ahmadi A, Najafi M, Farhood B, et al., 2018, Transforming Growth Factor-β Signaling: Tumorigenesis and Targeting for Cancer Therapy. J Cell Physiol, 234(8): 12173–12187.

Zhao M, Mishra L, Deng C-X, 2018, The Role of TGF-β/SMAD4 Signaling in Cancer. Int J Biol Sci, 14(2): 111–123.

Korkut A, Zaidi S, Kanchi RS, et al., 2018, A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily. Cell Syst, 7(4): 422–437.

Ozato K, Shin D-M, Chang T-H, et al., 2008, TRIM Family Proteins and Their Emerging Roles in Innate Immunity. Nat Rev Immunol, 8(11): 849–860.

Joazeiro CA, Weissman AM, 2000, RING Finger Proteins: Mediators of Ubiquitin Ligase Activity. Cell, 102(5): 549–552.

Inoue Y, Imamura T, 2008, Regulation of TGF-Beta Family Signaling by E3 Ubiquitin Ligases. Cancer Sci, 99(11): 2107–2112.

Hatakeyama S, 2017, TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis. Trends Biochem Sci, 42(4): 297–311.

Fitzgerald S, Espina V, Liotta L, et al., 2018, Stromal TRIM28-Associated Signaling Pathway Modulation within the Colorectal Cancer Microenvironment. J Transl Med, 16(1): 89.

Calon A, Lonardo E, Berenguer-Llergo A, et al., 2015, Stromal Gene Expression Defines Poor-Prognosis Subtypes in Colorectal Cancer. Nat Genet, 47(4): 320–329.

Khetchoumian K, Teletin M, Mark M, et al., 2004, TIF1delta, a Novel HP1-Interacting Member of the Transcriptional Intermediary Factor 1 (TIF1) Family Expressed by Elongating Spermatids. J Biol Chem, 279(46): 48329–48341.

Chen L, Muñoz-Antonia T, Cress WD, 2014, Trim28 Contributes to EMT via Regulation of E-Cadherin and N-Cadherin in Lung Cancer Cell Lines. PLoS One, 9(7): e101040.

Huntley S, Baggott DM, Hamilton AT, et al., 2006, A Comprehensive Catalog of Human KRAB-Associated Zinc Finger Genes: Insights into the Evolutionary History of a Large Family of Transcriptional Repressors. Genome Res, 16(5): 669–677.

Imbeault M, Helleboid P-Y, Trono D, 2017, KRAB Zinc-Finger Proteins Contribute to the Evolution of Gene Regulatory Networks. Nature, 543(7646): 550–554.

Kijanka G, Hector S, Kay EW, et al., 2010, Human IgG Antibody Profiles Differentiate between Symptomatic Patients with and without Colorectal Cancer. Gut, 59(1): 69–78.

Hector S, Chen H, Kijanka G, et al., 2012, A Reverse-ELISA for the Detection of TRIM28/KAP1 serum Autoantibodies in Colorectal Cancer Patients. Acta Oncol, 51(3): 394–396.

Lupo A, Cesaro E, Montano G, et al., 2013, KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions. Curr Genomics, 14(4): 268–278.

Tadepally HD, Burger G, Aubry M, 2008, Evolution of C2H2-Zinc Finger Genes and Subfamilies in Mammals: Species-Specific Duplication and Loss of Clusters, Genes and Effector Domains. BMC Evol Biol, 8: 176.

Sabater L, Ashhab Y, Caro P, et al., 2002, Identification of a KRAB-Containing Zinc Finger Protein, ZNF304, by AU-Motif-Directed Display Method and Initial Characterization in Lymphocyte Activation. Biochem Biophys Res Commun, 293(3): 1066–1072.

Serra RW, Fang M, Park SM, et al., 2014, A KRAS-Directed Transcriptional Silencing Pathway that Mediates the CpG Island Methylator Phenotype. Elife, 3: e02313.

Aslan B, Monroig P, Hsu M-C, et al., 2015, The ZNF304-Integrin Axis Protects Against Anoikis in Cancer. Nat Commun, 6: 7351.

Tse JWT, Jenkins LJ, Chionh F, et al., 2017, Aberrant DNA Methylation in Colorectal Cancer: What Should We Target? Trends Cancer, 3(10): 698–712.

Puisieux A, Brabletz T, Caramel J, 2014, Oncogenic Roles of EMT-Inducing Transcription Factors. Nat Cell Biol, 16(6): 488–494.

Thiery JP, 2002, Epithelial-Mesenchymal Transitions in Tumour Progression. Nat Rev Cancer, 2(6): 442–454.

Lambert AW, Pattabiraman DR, Weinberg RA, 2017, Emerging Biological Principles of Metastasis. Cell, 168(4): 670–691.

Fitzgerald S, Sheehan KM, O’Grady A, et al., 2013, Relationship between Epithelial and Stromal TRIM28 Expression Predicts Survival in Colorectal Cancer Patients. J Gastroenterol Hepatol, 28(6): 967–974.