It has been suggested that the placental gene PEG10 may have a role in the neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy.

Kim et al. used a unique model of enzalutamide resistance (ENZR) and neuroendocrine differentiation to study PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42D^ENZR and 42F^ENZR compared with LNCaP and castration-resistant 16D^CRPC cells.

ENZR cell lines with positive terminal neuroendocrine marker status displayed higher baseline expression of PEG10 compared with LNCaP and 16D^CRPC. Antagonism of AR activity increased PEG10 expression, followed by an increase in terminal neuroendocrine markers. Conversely, stimulating R activity via androgen supplementation reversed PEG10 and neuroendocrine marker expression in a time- and dose-dependent manner.

These results were supported by human data showing that PEG10 expression is highest in neuroendocrine prostate cancer (NEPC) and that an AR-dependent gene (for prostate-specific antigen) is negatively correlated with PEG10 in adenocarcinoma. Furthermore, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression.

While PEG10 did not drive NEPC, its knockdown reduced neuroendocrine markers in the cell lines. Moreover, PEG10 knockdown in vitro and in vivo attenuated tumour growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates neuroendocrine markers in ENZR cells, and that targeting PEG10 in advanced prostate cancer with neuroendocrine features may yield therapeutic potential.

Read the full article in Journal of Molecular Endocrinology 63 39–49