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

Mcdonald J, Diab N, Arthofer E, Hadley M, Kanholm T, Rentia U, Gomez S, Yu A, Grundy EE, Cox O, Topper MJ, Xing X, Strissel P, Strick R, Wang T, Baylin SB, Chiappinelli KB (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Cancer Research American Association for Cancer Research

Book Volume: 81

Pages Range: 5176-5189

Journal Issue: 20

DOI: 10.1158/0008-5472.CAN-20-4243

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.

Authors with CRIS profile

Pamela Strissel Medizinische Fakultät Reiner Strick Medizinische Fakultät

Involved external institutions

George Washington University (GWU) US United States (USA) (US) Johns Hopkins University (JHU) US United States (USA) (US) Washington University in St. Louis US United States (USA) (US)

How to cite

APA:

Mcdonald, J., Diab, N., Arthofer, E., Hadley, M., Kanholm, T., Rentia, U.,... Chiappinelli, K.B. (2021). Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner. Cancer Research, 81(20), 5176-5189. https://doi.org/10.1158/0008-5472.CAN-20-4243

MLA:

Mcdonald, James, et al. "Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner." Cancer Research 81.20 (2021): 5176-5189.

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