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 KossaiJuan Miguel Mosquera, Mark A. Rubin, Himisha Beltran, Amina Zoubeidi, Yuzhuo Wang, Martin E. Gleave, Colin C. Collins

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)922-936
Number of pages15
JournalCell Reports
Volume12
Issue number6
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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