Roxana Farokhnia

Background: Uterine cervical cancer (UCC) is the 4th most common cancer in women, and nearly all cases are caused by a human papillomavirus (HPV) infection.¹ Although prevention and early detection of UCC are available through vaccines and outpatient diagnostic tests, some cases of UCC are not detected until later stages when the therapeutic interventions become limited.² Worldwide, 75-80% of men and women have been infected with HPV, however, the progression of this infection into UCC is highly influenced by epigenetic changes.^1,3,4 Although there are many epigenetic modifications in the progression of UCC, one of current interest is DNA methylation because it occurs early in the development of the disease.⁵ Identifying the sites and mechanisms of DNA methylation in UCC progression is a promising approach to developing early diagnostic measures and potential therapeutics.

Objective: This narrative review explored the progress made in identifying DNA methylation sites unique to UCC, the mechanism behind DNA methylation and cancer progression, and the therapeutic approaches that arise from this knowledge.

Search Methods: An online search in the PubMed database was conducted from 2018-2022 using the following key words: epigenetic DNA methylation, human papillomavirus, HPV, uterine cervical cancer, cervical cancer, and therapies. In addition, the references and “similar articles” section were used to identify relevant literature.

Results:The results of this study identified promising diagnostic sites that target high-risk cervical cancer. One site is the SEPT9 gene involved in UCC progression, and hypermethylation of SEPT9 increases irradiation resistance which decreases patients’ sensitivity to treatment.⁶ Also, Cpg sites for the high-risk strains HPV16 and HPV18 were identified with their shared common pathways. This can serve as providing new diagnostic sites or novel pathways to develop innovative therapies that would target both strains.⁵ Also, methylation site subgroups based on DNA methylation levels were created and helped identify likely survival outcomes based on each subgroup which can improve estimations of prognosis.⁷ The therapeutic approaches identified focused on targeting DNA methylation machinery to downregulate the expression of DNA methyl transferase by using known anti-carcinogens Green tea polyphenol epigallocatechin gallate (EGCG), eugenol, and amarogentin to upregulate tumor suppressor activity.⁸ Another approach is to introduce an exogenous mimic treatment of microRNA-138 (miR-138) to upregulate its tumor suppressor activity.⁹

Conclusions: Developing UCC diagnostics based on DNA methylation sites can increase the detection of UCC in earlier stages of progression and share prognostic information on survival outcomes and potential response to radiation treatment. In addition, developing therapeutic approaches focusing on downregulating DNA methylation machinery has shown a reduction in tumor size in mouse models when focusing on demethylating miR-138.⁸ Some further opportunities for exploration in this realm include scaling up therapeutic approaches to larger animal models or experimental human trials, applying novel DNA methylation sites to current HPV UCC diagnostic tests, and performing sensitivity and specificity tests of these diagnostic markers at different stages of disease progression to improve accuracy in diagnosis.

Works Cited:

1. Da Silva MLR, De Albuquerque BHDR, Allyrio TAMF, et al. The role of HPV-induced epigenetic changes in cervical carcinogenesis (Review). Biomed Rep. 2021;15(1):60. doi:10.3892/br.2021.1436
2. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019;393(10167):169-182. doi:10.1016/S0140-6736(18)32470-X
3. Yousefi Z, Aria H, Ghaedrahmati F, et al. An Update on Human Papilloma Virus Vaccines: History, Types, Protection, and Efficacy. Front Immunol. 2022;12:805695. Published 2022 Jan 27. doi:10.3389/fimmu.2021.805695
4. Albert E, Laimins L. Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors. Viruses. 2020;12(7):744. Published 2020 Jul 10. doi:10.3390/v12070744
5. Ma Y, Wang C, Shi M, et al. Searching for the methylation sites involved in human papillomavirus type 16 and 18‑positive women with cervical cancer. Mol Clin Oncol. 2022;17(4):149. Published 2022 Sep 2. doi:10.3892/mco.2022.2582
6. ​​Jiao X, Zhang S, Jiao J, et al. Promoter methylation of SEPT9 as a potential biomarker for early detection of cervical cancer and its overexpression predicts radioresistance. Clin Epigenetics. 2019;11(1):120. Published 2019 Aug 19. doi:10.1186/s13148-019-0719-9
7. Yang S, Wu Y, Wang S, et al. HPV-related methylation-based reclassification and risk stratification of cervical cancer. Mol Oncol. 2020;14(9):2124-2141. doi:10.1002/1878-0261.12709
8. Pal D, Sur S, Roy R, Mandal S, Kumar Panda C. Epigallocatechin gallate in combination with eugenol or amarogentin shows synergistic chemotherapeutic potential in cervical cancer cell line. J Cell Physiol. 2018;234(1):825-836. doi:10.1002/jcp.26900
9. Chen R, Gan Q, Zhao S, et al. DNA methylation of miR-138 regulates cell proliferation and EMT in cervical cancer by targeting EZH2. BMC Cancer. 2022;22(1):488. Published 2022 May 3. doi:10.1186/s12885-022-09477-5