The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer

•Placental gene PEG10 is highly expressed in neuroendocrine prostate cancer (NEPC)•PEG10 is dynamically regulated by AR and E2F/RB during NEPC development•Distinct isoforms of PEG10 promote proliferation and invasion of NEPC cells•PEG10 represents a specific therapeutic target for NEPC

SummaryMore 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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