Epigenetic therapies in ovarian cancer alter repetitive element expression in a TP53-dependent manner
Journal
Cancer Research
Journal Volume
81
Journal Issue
20
Date Issued
2021
Author(s)
McDonald J.I
Diab N
Arthofer E
Hadley M
Kanholm T
Rentia U
Gomez S
Grundy E.E
Cox O
Topper M.J
Xing X
Strissel P.L
Strick R
Wang T
Baylin S.B
Chiappinelli K.B.
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. © 2021 American Association for Cancer Research Inc.. All rights reserved.
Subjects
DNA methylation; Histone Acetylation; Interferon Signaling; Ovarian Cancer; P53; Retrotransposon Transcription
SDGs
Other Subjects
DNA methyltransferase inhibitor; double stranded RNA; histone deacetylase inhibitor; antineoplastic antimetabolite; azacitidine; histone deacetylase inhibitor; protein p53; TP53 protein, human; tumor marker; A2780 cell line; animal experiment; animal model; Article; cancer immunotherapy; CD8+ T lymphocyte; controlled study; DNA methylation; DNA transcription; epigenetics; female; gene expression; gene locus; gene mutation; gene therapy; histone acetylation; human; human cell; immune signaling; interferon signaling; Kuramochi cell line; natural killer cell; nonhuman; ovarian cancer cell line; ovary cancer; retroposon; SK-OV-3 cell line; transcription regulation; tumor suppressor gene; upregulation; apoptosis; cell proliferation; drug effect; gene expression regulation; genetic epigenesis; genetics; metabolism; nucleotide repeat; ovary tumor; pathology; tumor cell culture; Antimetabolites, Antineoplastic; Apoptosis; Azacitidine; Biomarkers, Tumor; Cell Proliferation; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Ovarian Neoplasms; Repetitive Sequences, Nucleic Acid; Tumor Cells, Cultured; Tumor Suppressor Protein p53
Type
journal article