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

Cancer Cell. 2016 Oct 10;30(4):563-577. doi: 10.1016/j.ccell.2016.09.005.

Abstract

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 overexpression 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 overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.

Keywords: Aurora kinase A; EZH2; N-Myc; castration-resistant prostate adenocarcinoma; genetically engineered mouse; neuroendocrine prostate cancer; prostate cancer organoid.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Genes, myc
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • N-Myc Proto-Oncogene Protein / biosynthesis
  • N-Myc Proto-Oncogene Protein / genetics*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroendocrine Tumors / drug therapy
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Transcription, Genetic

Substances

  • Azepines
  • MLN 8237
  • MYCN protein, human
  • MYCN protein, mouse
  • N-Myc Proto-Oncogene Protein
  • Protein Kinase Inhibitors
  • Pyrimidines
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse