Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner.

Abstract

Epithelial ovarian carcinomas are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the ovarian carcinoma epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and natural killer cells to fight ovarian carcinoma in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an IFN response. To understand which REs are affected by epigenetic therapies in ovarian carcinoma, we assessed the effect of DNMTi and HDACi on ovarian carcinoma cell lines and patient samples. Subfamily-level (TEtranscripts) and individual locus-level (Telescope) analysis of REs showed that DNMTi treatment upregulated more REs than HDACi treatment. Upregulated REs were predominantly LTR and SINE subfamilies, and SINEs exhibited the greatest loss of DNA methylation upon DNMTi treatment. Cell lines with TP53 mutations exhibited significantly fewer upregulated REs with epigenetic therapy than wild-type TP53 cell lines. This observation was validated using isogenic cell lines; the TP53-mutant cell line had significantly higher baseline expression of REs but upregulated fewer upon epigenetic treatment. In addition, p53 activation increased expression of REs in wild-type but not mutant cell lines. These data give a comprehensive, genome-wide picture of RE chromatin and transcription-related changes in ovarian carcinoma after epigenetic treatment and implicate p53 in RE transcriptional regulation. SIGNIFICANCE: This study identifies the repetitive element targets of epigenetic therapies in ovarian carcinoma and indicates a role for p53 in this process.

• Authors: James I McDonald, Noor Diab, Elisa Arthofer, Melissa Hadley, Tomas Kanholm, Uzma Rentia, Stephanie Gomez, Angela Yu, Erin E Grundy, Olivia Cox, Michael J Topper, Xiaoyun Xing, Pamela L Strissel, Reiner Strick, Ting Wang, Stephen B Baylin, Katherine B Chiappinelli
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 20 Pg. 5176-5189 (10 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34433584 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antimetabolites, Antineoplastic
• Biomarkers, Tumor
• Histone Deacetylase Inhibitors
• TP53 protein, human
• Tumor Suppressor Protein p53
• Azacitidine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis
• Azacitidine (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Repetitive Sequences, Nucleic Acid
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)