N-Myc induces an EZH2-mediated transcriptional program driving Neuroendocrine Prostate Cancer

The transition from castration resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) is emerging as an important mechanism of treatment resistance. NEPC are associated with over-expression and gene amplification of MYCN (encoding N-Myc). N-Myc is a bona fide driver oncogene in several rare tumor types, but its role in prostate cancer progression is not well established. Integrating a novel genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc over-expression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC tumors which includes an abrogation of AR signaling and induction of Polycomb Repressive Complex 2 signaling and that N-Myc interacts with AR and this interaction depends on Enhancer of Zeste Homolog 2. Altogether, our data shows that N-Myc drives the neuroendocrine phenotype in prostate cancer. RNA sequencing of mice prostates or human cell lines expressing N-Myc; ChIp-Seq of H3K27me3 +/- N-Myc in human cell line; RNA sequencing of human cell line expressing N-Myc after EZH2 knockdown or treatment with GSK343.