Androgen Deprivation Induces Neuroendocrine Phenotypes in Prostate Cancer Cells Through CREB1/EZH2-Mediated Downregulation of Rest

Authors

Dayong Zheng
Yan Zhang
Sukjin Yang
Ning Su
Michael Bakhoum
Guoliang Zhang
Samira Naderinezhad
Zhengmei Mao
Zheng Wang
Ting Zhou
Wenliang Li

Publication Date

5-22-2024

Journal

Cell Death Discovery

Abstract

Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.

DOI

10.1038/s41420-024-02031-1

PMID

38777812

PMCID

PMC11111810

PubMedCentral® Posted Date

5-22-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes