Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress

Yiji Liao, Chen Hao Chen, Tengfei Xiao, Bárbara de la Peña Avalos, Eloise V. Dray, Changmeng Cai, Shuai Gao, Neel Shah, Zhao Zhang, Avery Feit, Pengya Xue, Zhijie Liu, Mei Yang, Ji Hoon Lee, Han Xu, Wei Li, Shenglin Mei, Roodolph S. Pierre, Shaokun Shu, Teng FeiMelissa Duarte, Jin Zhao, James E. Bradner, Kornelia Polyak, Philip W. Kantoff, Henry Long, Steven P. Balk, X. Shirley Liu, Myles Brown, Kexin Xu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Article numbere2105898119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 18 2022


  • Cancer therapy
  • DNA damage repair
  • EZH2 inhibitors
  • Mechanism of drug action

ASJC Scopus subject areas

  • General


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