EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer

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Abstract

Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells. Mechanistically, upon oxidative stress or alkylating DNA damage, PARP1 interacts with and attaches poly-ADP-ribose (PAR) chains to EZH2. PARylation of EZH2 by PARP1 then induces PRC2 complex dissociation and EZH2 downregulation, which in turn reduces EZH2-mediated H3 trimethylation. In contrast, inhibition of PARP by PARPi attenuates alkylating DNA damage-induced EZH2 downregulation, thereby promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARPi-untreated cells. Moreover, the addition of an EZH2 inhibitor sensitizes the BRCA-mutant breast cells to PARPi. Thus, these results may provide a rationale for combining PARP and EZH2 inhibition as a therapeutic strategy for BRCA-mutated breast and ovarian cancers.

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Acknowledgements

This study was supported in part by the following: the National Institutes of Health (CA211615 and CCSG CA016672); Patel Memorial Breast Cancer Endowment Fund; National Breast Cancer Foundation, Inc.; Breast Cancer Research Foundation; The University of Texas MD Anderson Cancer Center-China Medical University and Hospital Sister Institution Fund; Ministry of Science and Technology; International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 105-2911-I-002-302); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW106-TDU-B-212-144003); Center for Biological Pathways; The UT Southwestern Endowed Scholar Program, the Welch Foundation (I-1800) and National Institutes of Health (GM114160) to YY. Dr YY is a Virginia Murchison Linthicum Scholar in Medical Research and a CPRIT Scholar in Cancer Research.

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Correspondence to M-C Hung.

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Yamaguchi, H., Du, Y., Nakai, K. et al. EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer. Oncogene 37, 208–217 (2018) doi:10.1038/onc.2017.311

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