N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer

Abstract

Summary The transition from castration resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with over-expression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a 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. This includes an abrogation of AR signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

“…We also studied the epigenetic networks and their response phoma (40), breast (61,62), myeloid (63), and prostate cancers (64). More recently, Dardenne et al described a MYCN-induced, EZH2-mediated transcriptional program in neuroendocrine prostate cancer (65). Despite the fact that massively parallel sequencing of neuroblastoma tumors has not revealed frequent mutations or focal amplifications of EZH2, recently published work has suggested a role for EZH2 in neuroblastoma (49,66,67).…”

The Expanding World of N-MYC–Driven Tumors

“…1; refs. 35,46,48,49,111). N-MYC is overexpressed in the majority of NEPC cases, but there is a spectrum of N-MYC expression in CRPC samples, with 20% of CRPC tumors demonstrating transcript levels in the range of NEPC (46,49).…”

“…Ectopic MYCN induction in human prostate adenocarcinoma (LNCaP) cells that have high intrinsic C-MYC expression resulted in a dramatic downregulation of MYC mRNA and a transformation to a NEPC-like phenotype (46). The NEPC transcriptional program includes an abrogation of AR signaling, enhanced AKT and epithelial-mesenchymal transition signaling, increased EZH2 levels, and activity and expression of stem cell-related gene signatures and neuroendocrine markers.…”

“…MYC overexpression is an early event that occurs in lesions of high-grade prostatic intraepithelial neoplasia and localized prostatic adenocarcinomas, suggesting that C-MYC contributes to the initiation and progression of the disease (50). MYCN, on the other hand, is amplified and overexpressed in late-stage prostate cancer (35,46,49,111) and, based on data from human and mouse model systems, can drive the progression from CRPC toward poorly differentiated NEPC ( Fig. 1; refs.…”

“…CRPC tumors with high N-MYC levels also display features of NEPC (e.g., low AR signaling and expression of chromogranin A; refs. 46,49).…”