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Elucidation of AR impact on the paternally expressed Gene 10 (PEG10) in Enzalutamide-resistant prostate cancer

University of British Columbia

Despite advances in therapeutics, castration resistant prostate cancer (CRPC) continues to be a major problem due to ongoing androgen receptor (AR) activity driving disease progression. This lack of control of AR inhibition in drug resistant CRPC may reflect a shift in the natural history of classically “AR-driven” disease to a “AR non-driven” phenotype, characterized by low circulating levels of prostate specific antigen (PSA) despite high metastatic burden in soft tissues. This hypothesis is supported by recent data from the Stand up to Cancer-Prostate Cancer Foundation East Coast and West Coast Dream Team (SU2C) indicating up to 27% of CRPC patients resistant to AR pathway inhibitors, including ENZ or ABI, develop an AR non-driven disease. Notably, our pre-clinical model of ENZ-R also reflects the clinical distribution of disease heterogeneity. We have shown that while 75% of ENZ-R tumors recur in vivo with AR re-activation and rising PSA, 25% of tumors show downregulation of canonical AR target genes and maintain an AR non-driven phenotype. Analysis of ENZ-R cells using RNAseq revealed that ENZ-R cells with downregulation of canonical pathway and NE phenotype up-regulate the paternally expressed gene 10 (PEG10). PEG10 is a retrotransposon-derived gene that was recently reported to be upregulated in neuroendocrine prostate cancer (NEPC) and regulates cell survival and metastasis in NEPC. However the underlying mechanisms by which PEG10 is regulated in ENZ-R and NEPC remain unexplored. We found that AR negatively regulates PEG10 and that activated AR directly binds to the PEG10 promoter and suppresses its expression while ENZ inhibits AR activity which allows for the NE differentiation to commence in CRPC and ENZ-R cell lines. In the next step, we investigated whether PEG10 is a potential target of NEPC progression in CRPC and ENZ-R cell lines. Through our experiments, we demonstrated that targeting PEG10 reduces cell proliferation in vitro, while knocking down PEG10 in vivo attenuates tumor growth. The results justify PEG10 as potential therapeutic target for NEPC.

Text

2018-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/59301

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/