Journal Article

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

Du, Y, Chang, W-C, Nakai, K, Yao, J, Ding, M, Hortobagyi, G N, Yamaguchi, H, Chang, S-S, Chen, C-H, Yu, Y, Jiao, S, Hsu, J L, Hung, M-C, Nie, L, Wei, Y

2018

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 38/77 / 631/67/1347 / 631/67/1517/1709 / 64/60 / 82/80 / Adenosine diphosphate / ADP-Ribosylation - drug effects / Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / BRCA1 Protein - genetics / BRCA2 Protein - genetics / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer cells / Care and treatment / Cell Biology / Cell Line, Tumor / Cell proliferation / Clinical trials / Diagnosis / DNA Damage / DNA replication / Down-Regulation / Drug Resistance, Neoplasm / Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / Enzymes / Female / Gene Silencing / Health aspects / Human Genetics / Humans / Internal Medicine / Lysine / Medicine / Medicine & Public Health / Mice / Mice, Nude / Oncology / original-article / Ovarian cancer / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - genetics / Ovarian Neoplasms - pathology / Oxidative stress / Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Polymerase chain reaction / Ribose / Ribosylation / RNA, Small Interfering - metabolism / Stem cells / Targeted cancer therapy / Xenograft Model Antitumor Assays