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

Dardenne, Etienne ; Beltran, Himisha ; Benelli, Matteo ; Gayvert, Kaitlyn ; Berger, Adeline ; Puca, Loredana ; Cyrta, Joanna ; Sboner, Andrea ; Noorzad, Zohal ; MacDonald, Theresa ; Cheung, Cynthia ; Yuen, Ka Shing ; Gao, Dong ; Chen, Yu ; Eilers, Martin ; Mosquera, Juan-Miguel ; Robinson, Brian D. ; Elemento, Olivier ; Rubin, Mark A. ; Demichelis, Francesca ; Rickman, David S.

Cancer cell, 2016-10, Vol.30 (4), p.563-577 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer
Autor: Dardenne, Etienne ; Beltran, Himisha ; Benelli, Matteo ; Gayvert, Kaitlyn ; Berger, Adeline ; Puca, Loredana ; Cyrta, Joanna ; Sboner, Andrea ; Noorzad, Zohal ; MacDonald, Theresa ; Cheung, Cynthia ; Yuen, Ka Shing ; Gao, Dong ; Chen, Yu ; Eilers, Martin ; Mosquera, Juan-Miguel ; Robinson, Brian D. ; Elemento, Olivier ; Rubin, Mark A. ; Demichelis, Francesca ; Rickman, David S.
Assuntos: Animals ; Aurora kinase A ; Azepines - pharmacology ; castration-resistant prostate adenocarcinoma ; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors ; Enhancer of Zeste Homolog 2 Protein - genetics ; Enhancer of Zeste Homolog 2 Protein - metabolism ; EZH2 ; Genes, myc ; genetically engineered mouse ; Heterografts ; Humans ; Male ; Mice ; Mice, Transgenic ; N-Myc ; N-Myc Proto-Oncogene Protein - biosynthesis ; N-Myc Proto-Oncogene Protein - genetics ; N-Myc Proto-Oncogene Protein - metabolism ; neuroendocrine prostate cancer ; Neuroendocrine Tumors - drug therapy ; Neuroendocrine Tumors - genetics ; Neuroendocrine Tumors - metabolism ; Neuroendocrine Tumors - pathology ; prostate cancer organoid ; 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
É parte de: Cancer cell, 2016-10, Vol.30 (4), p.563-577
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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These authors contributed equally to this work.
Descrição: 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. [Display omitted] •N-Myc drives the NEPC phenotype and associated molecular program•N-Myc abrogates AR signaling, which results in enhanced AKT activity•N-Myc redirects EZH2 activity and sensitizes cells to EZH2 inhibitors•N-Myc interacts with Aurora-A, which facilitates N-Myc target gene expression Dardenne et al. demonstrate that N-Myc overexpression in pre-clinical models drives aggressive prostate cancer that mimics human neuroendocrine prostate cancer, including reduced AR signaling and enhanced PRC2 target gene repression, and sensitizes cells to an Aurora-A inhibitor and EZH2 SET domain inhibitors.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

United States: Elsevier Inc

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