Epigenetic therapies in ovarian cancer alter repetitive element expression in a TP53-dependent manner

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Epithelial ovarian carcinomas (OC) are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the OC epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and NK cells to fight OC 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 interferon response. To understand which REs are affected by epigenetic therapies in OC, we assessed the effect of DNMTi and HDACi on OC 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 OC after epigenetic treatment and implicate p53 in RE transcriptional regulation.

Original languageEnglish
JournalCancer research
Volume81
Issue number20
DOIs
StatePublished - Oct 15 2021

Keywords

  • DNA methylation
  • Histone Acetylation
  • Interferon Signaling
  • Ovarian Cancer
  • P53
  • Retrotransposon Transcription

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