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
  • 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: [email protected].
  • 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: [email protected].
PMID: 26235627 DOI: 10.1016/j.celrep.2015.07.012
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.