PEG10 is associated with treatment-induced neuroendocrine prostate cancer. (July 2019)

• Record Type: Journal Article
• Authors: Kim, Soojin; Thaper, Daksh; Bidnur, Samir; Toren, Paul; Akamatsu, Shusuke; Bishop, Jennifer L; Colins, Colin; Vahid, Sepideh; Zoubeidi, Amina
• Is Part Of: Journal of molecular endocrinology. Volume 63:Number 1(2019)
• Page Start: 39
• Page End: 49
• Publication Date: 2019-07
• Subjects: prostate cancer -- neuroendocrine -- treatment resistance -- PEG10 -- androgen receptor; Molecular endocrinology -- Periodicals; Endocrinology -- Periodicals; 616.407
• DOI: 10.1530/JME-18-0226
• Languages: English
• ISSNs: 0952-5041

Abstract

Abstract : Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42D ENZR and 42F ENZR compared to LNCaP and castration-resistant 16D CRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16D CRPC . Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro - and in vivo -attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.