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: 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.

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.

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