Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress.

Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.
Competing Interests: Competing interest statement: N.S. receives research grant funding from AstraZeneca. J.E.B. is an executive and shareholder of Novartis AG and has been a founder and shareholder of SHAPE (acquired by Medivir), Acetylon (acquired by Celgene), Tensha (acquired by Roche), Syros, Regency, and C4 Therapeutics. P.W.K. serves on the scientific advisory board (SAB) of BIND Biosciences, BN Immunotherapeutics, GE Healthcare, Janssen, New England Research Institutes, OncoCellMDX, Progenity, Sanofi, and Thermo Fisher. He shares investment interests in Context Therapeutics, Druggability Technologies Holdings Ltd. (DRGT), Placon, Seer Biosciences, and Tarveda Therapeutics. He also serves on the Data and Safety Monitoring Board (DSMB) of Genetch and Merck. X.S.L. is a cofounder, board member, SAB, and consultant of GV20 Oncotherapy and its subsidiaries. M.B. is a consultant to and receives sponsored research support from Novartis and is a consultant to MPM Capital and serves on the SAB of Kronos Bio, H3 Biomedicine, and GV20 Oncotherapy.
(Copyright © 2022 the Author(s). Published by PNAS.)