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

TitleN-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsDardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, Cyrta J, Sboner A, Noorzad Z, MacDonald T, Cheung C, Yuen KShing, Gao D, Chen Y, Eilers M, Mosquera J-M, Robinson BD, Elemento O, Rubin MA, Demichelis F, Rickman DS
JournalCancer Cell
Volume30
Issue4
Pagination563-577
Date Published2016 10 10
ISSN1878-3686
KeywordsAnimals, Azepines, Enhancer of Zeste Homolog 2 Protein, Genes, myc, Heterografts, Humans, Male, Mice, Mice, Transgenic, N-Myc Proto-Oncogene Protein, Neuroendocrine Tumors, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Protein Kinase Inhibitors, Pyrimidines, Signal Transduction, Transcription, Genetic
Abstract

The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancerĀ (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.

DOI10.1016/j.ccell.2016.09.005
Alternate JournalCancer Cell
PubMed ID27728805
PubMed Central IDPMC5540451
Grant ListR01 CA179100 / CA / NCI NIH HHS / United States
R01 CA193837 / CA / NCI NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K08 CA140946 / CA / NCI NIH HHS / United States
R01 CA116337 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States