1. Academic Validation
  2. The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer

The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer

  • Cell Rep. 2015 Aug 11;12(6):922-36. doi: 10.1016/j.celrep.2015.07.012.
Shusuke Akamatsu 1 Alexander W Wyatt 1 Dong Lin 2 Summer Lysakowski 1 Fan Zhang 1 Soojin Kim 1 Charan Tse 1 Kendric Wang 1 Fan Mo 1 Anne Haegert 1 Sonal Brahmbhatt 1 Robert Bell 1 Hans Adomat 1 Yoshihisa Kawai 1 Hui Xue 3 Xin Dong 3 Ladan Fazli 1 Harrison Tsai 4 Tamara L Lotan 4 Myriam Kossai 5 Juan Miguel Mosquera 5 Mark A Rubin 5 Himisha Beltran 6 Amina Zoubeidi 1 Yuzhuo Wang 2 Martin E Gleave 7 Colin C Collins 8
Affiliations

Affiliations

  • 1 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
  • 2 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
  • 3 Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
  • 4 Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
  • 5 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY 10065, USA.
  • 6 Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY 10065, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 7 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada. Electronic address: m.gleave@ubc.ca.
  • 8 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada. Electronic address: ccollins@prostatecentre.com.
Abstract

More potent targeting of the Androgen Receptor (AR) in advanced prostate Cancer is driving an increased incidence of neuroendocrine prostate Cancer (NEPC), an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-β signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target.

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