The therapeutic effect of EZH2 inhibitors in targeting human papillomavirus associated cervical cancer

Article

Vidalina, D., Ghali, L., Kassouf, N., Li, S., Li, D. and Wen, X. 2025. The therapeutic effect of EZH2 inhibitors in targeting human papillomavirus associated cervical cancer. Current Issues in Molecular Biology. 47 (12), p. 990. https://doi.org/10.3390/cimb47120990
TypeArticle
TitleThe therapeutic effect of EZH2 inhibitors in targeting human papillomavirus associated cervical cancer
AuthorsVidalina, D., Ghali, L., Kassouf, N., Li, S., Li, D. and Wen, X.
Abstract

High-risk human papillomavirus (HPV) is a crucial risk factor in the development of cervical cancer, where epigenetic modifications and epithelial–mesenchymal transition (EMT) processes have been implicated in cancer progression and metastasis. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is frequently overexpressed in HPV-associated cervical cancers and has been linked to tumour progression. However, there is still no consensus on the mechanisms of their action and their effectiveness on HPV-associated cancers. This study aimed to investigate whether EZH2 inhibitors (EPZ6438 and ZLD1039) can be effective in managing cervical cancer with less toxic effects than the conventional chemotherapeutic drug cisplatin. Proliferation assay and flow cytometry results showed that EZH2 inhibitors effectively induced apoptosis and arrested cells in G0/G1 phase in both HPV+ and HPV- cervical cancer cells. Both inhibitors downregulated the expression of EZH2 and HPV16 E6/E7 at mRNA and protein levels whilst upregulating expressions of p53 and Rb and epithelial markers. In summary, both EZH2 inhibitors showed therapeutic potential in comparison to cisplatin based on cellular and molecular readouts. Additionally, EPZ6438 showed a greater efficacy and higher sensitivity towards HPV+ cells, which was further supported by preliminary in vivo results from the chorioallantoic membrane assay.

KeywordsEZH2 inhibitor; HPV16; cervical cancer; epigenetics
Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
Research GroupCentre for Investigative and Diagnostic Oncology
PublisherMDPI
JournalCurrent Issues in Molecular Biology
ISSN
Electronic1467-3045
Publication dates
Online27 Nov 2025
Print27 Nov 2025
Publication process dates
Submitted31 Oct 2025
Accepted24 Nov 2025
Deposited03 Dec 2025
Output statusPublished
Publisher's version
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File Access Level
Open
Copyright Statement

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)https://doi.org/10.3390/cimb47120990
PubMed Central IDPMC12732196
Web of Science identifierWOS:001646262300001
National Library of Medicine ID100931761
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Golder, M., Burleigh, D., Ghali, L., Feakins, R., Lunniss, P., Williams, N. and Navsaria, H. 2007. Longitudinal muscle shows abnormal relaxation responses to nitric oxide and contains altered levels of NOS1 and elastin in uncomplicated diverticular disease. Colorectal disease. 9 (3), pp. 218-228.
HPV8 early genes modulate differentiation and cell cycle of primary human adult keratinocytes.
Akgul, B., Ghali, L., Davies, D., Pfister, H., Leigh, I. and Storey, A. 2007. HPV8 early genes modulate differentiation and cell cycle of primary human adult keratinocytes. Clinical and experimental dermatology. 16 (7), pp. 590-599.
Granulosa cell survival and proliferation are altered in polycystic ovary syndrome
Das, M., Djahanbakhch, O., Hacihanefioglu, B., Saridogan, E., Ikram, M., Ghali, L., Raveendran, M. and Storey, A. 2008. Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 93 (3), pp. 881-887. https://doi.org/10.1210/jc.2007-1650
GLI1 repression of ERK activity correlates with colony formation and impaired migration in human epidermal keratinocytes
Neill, G., Harrison, W., Ikram, M., Williams, T., Bianchi, L., Nadenla, S., Green, J., Ghali, L., Frischauf, A., O'Toole, E., Aberger, F. and Philpott, M. 2008. GLI1 repression of ERK activity correlates with colony formation and impaired migration in human epidermal keratinocytes. Carcinogenesis. 29 (4), pp. 738-746. https://doi.org/10.1093/carcin/bgn037
Gonadotropins and prostate cancer: revisited.
Thwaini, A., Naase, M., Chinegwundon, F., Baithun, S., Ghali, L., Shergill, I. and Iles, R. 2006. Gonadotropins and prostate cancer: revisited. Urologia internationalis. 77 (4), pp. 289-296. https://doi.org/10.1159/000096330
Smooth muscle cholinergic denervation hypersensitivity in diverticular disease.
Ghali, L., Belai, A., Burleigh, D. and Golder, M. 2003. Smooth muscle cholinergic denervation hypersensitivity in diverticular disease. The Lancet. 361 (9373), pp. 1945-1951. https://doi.org/10.1016/S0140-6736(03)13583-0
Epidermal and hair follicle progenitor cells express melanoma-associated chondroitin sulfate proteoglycan core protein
Ghali, L., Wong, S., Tidman, N., Quinn, A., Philpott, M. and Leigh, I. 2004. Epidermal and hair follicle progenitor cells express melanoma-associated chondroitin sulfate proteoglycan core protein. Journal of investigative dermatology. 122 (2), pp. 433-442. https://doi.org/10.1046/j.0022-202X.2004.22207.x
FOXM1 is a downstream target of Gli1 in basal cell carcinomas
Teh, M., Wong, S., Neill, G., Ghali, L., Philpott, M. and Quinn, A. 2002. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Research. 62 (16), pp. 4773-4780.
Loss of protein kinase calpha expression may enhance the tumorigenic potential of Gli1 in basal cell carcinoma
Ghali, L., Green, J., Ikram, M. and Neill, G. 2003. Loss of protein kinase calpha expression may enhance the tumorigenic potential of Gli1 in basal cell carcinoma. Cancer Research. 63 (15), pp. 4692-4697.
Human granulosa-lutein cell in vitro production of progesterone, inhibin A, inhibin B, and activin A are dependent on follicular size and not the presence of the oocyte
Wen, S., Tozer, A., Li, D., Docherty, S., Al-Shawaf, T. and Iles, R. 2008. Human granulosa-lutein cell in vitro production of progesterone, inhibin A, inhibin B, and activin A are dependent on follicular size and not the presence of the oocyte. Fertility and Sterility. 89 (5), pp. 1406-1413. https://doi.org/10.1016/j.fertnstert.2007.03.086
Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte's ability to fertilize
Wen, S., Tozer, A., Butler, S., Bell, C., Docherty, S. and Iles, R. 2006. Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte's ability to fertilize. Fertility and Sterility. 85 (6), pp. 1723-1729. https://doi.org/10.1016/j.fertnstert.2005.11.058
Characteristics of populations of granulosa cells from individual follicles in women undergoing 'coasting' during controlled ovarian stimulation (COS) for IVF
Tozer, A., Iles, R., Iammarrone, E., Gillott, C., Wen, S., Al-Shawaf, T. and Grudzinskas, J. 2004. Characteristics of populations of granulosa cells from individual follicles in women undergoing 'coasting' during controlled ovarian stimulation (COS) for IVF. Human Reproduction. 19 (11), pp. 2561-2568. https://doi.org/10.1093/humrep/deh487