Cell Reports (Aug 2015)
The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer
- Shusuke Akamatsu,
- Alexander W. Wyatt,
- Dong Lin,
- Summer Lysakowski,
- Fan Zhang,
- Soojin Kim,
- Charan Tse,
- Kendric Wang,
- Fan Mo,
- Anne Haegert,
- Sonal Brahmbhatt,
- Robert Bell,
- Hans Adomat,
- Yoshihisa Kawai,
- Hui Xue,
- Xin Dong,
- Ladan Fazli,
- Harrison Tsai,
- Tamara L. Lotan,
- Myriam Kossai,
- Juan Miguel Mosquera,
- Mark A. Rubin,
- Himisha Beltran,
- Amina Zoubeidi,
- Yuzhuo Wang,
- Martin E. Gleave,
- Colin C. Collins
Affiliations
- Shusuke Akamatsu
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Alexander W. Wyatt
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Dong Lin
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Summer Lysakowski
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Fan Zhang
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Soojin Kim
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Charan Tse
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Kendric Wang
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Fan Mo
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Anne Haegert
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Sonal Brahmbhatt
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Robert Bell
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Hans Adomat
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Yoshihisa Kawai
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Hui Xue
- Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
- Xin Dong
- Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
- Ladan Fazli
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Harrison Tsai
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
- Tamara L. Lotan
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
- Myriam Kossai
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Mark A. Rubin
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Himisha Beltran
- Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY 10065, USA
- Amina Zoubeidi
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Yuzhuo Wang
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Martin E. Gleave
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- Colin C. Collins
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
- DOI
- https://doi.org/10.1016/j.celrep.2015.07.012
- Journal volume & issue
-
Vol. 12,
no. 6
pp. 922 – 936
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.
