ERR? impedes neuroendocrine prostate cancer development [ChIP-Seq]

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). The molecular mechanisms underlying the progression of CRPC toward NEPC remain incompletely understood and effective treatments remain to be discovered. Herein, we report that loss of the nuclear receptor ERR? promotes neuroendocrine differentiation in a Pten-deficient mouse model of prostate adenocarcinoma. These findings were recapitulated in advanced cellular and xenograft models of human prostate cancer (PCa). Critically, we show that ERR? gain-of-function can reverse instilled NEPC features accompanied by suppression of growth and oncogenic metabolic reprogramming. Activation of a neuroendocrine transcriptional program enabled by ERR? deficiency unveiled a targetable vulnerability exploited by combined pharmacological inhibition of EZH2 and RET kinase that effectively inhibited the growth of ERR?-deficient tumor organoids and cells. Collectively, our findings demonstrate that ERR? downregulation facilitates PCa adeno-to-neuroendocrine transformation and offer potential therapeutic strategies to prevent/treat the development of poor outcome NEPC. Overall design: ERR? ChIP-seq experiments were performed in engineered PTEN-ERR?+ (sgPTEN+ERR?) and PTEN-ERR?low (sgPTEN) DU145 cells, the latter used as a control for ERR? peak calling in PTEN-ERR?+ cells. DU145 cells have high PTEN and low ERR? status to which we generated PTEN-ERR?low cells by stably knocking out PTEN by CRISPR/Cas9 followed by lentivirus-mediated ERR? overexpression in PTEN-ERR?low cells to generate PTEN-ERR?+ cells. H3K27ac and H3K27me3 ChIP-seq experiments were performed in PTEN-ERR?+ (sgPTEN+ERR?) and PTEN-ERR?low (sgPTEN) DU145 cells and peaks were called using respective input controls.