Abstract
PRNCR1 and PCGEM1 bind the androgen receptor (AR) and promote AR target gene activation.
Major finding: PRNCR1 and PCGEM1 bind the androgen receptor (AR) and promote AR target gene activation.
Concept: These lncRNAs promote ligand-independent AR activity and castration-resistant prostate cancer growth.
Impact: Overexpression of PRNCR1 and PCGEM1 may drive castration resistance in prostate cancer.
Long noncoding RNAs (lncRNA) expression is sometimes deregulated in human cancers, but the functional consequences are often unclear. PRNCR1 is a lncRNA that is located in a prostate cancer susceptibility locus, and PCGEM is a prostate-specific lncRNA that is overexpressed in high-risk prostate cancer patients. Yang and colleagues performed native RNA immunoprecipitation in paired benign prostatic hyperplasias and prostate cancers and observed that PRNCR1 and PCGEM1 specifically interacted with the androgen receptor (AR) in prostate cancer samples. Knockdown of PRNCR1 abolished the interactions between both lncRNAs and AR, whereas PCGEM knockdown had no effect on the binding of PRNCR1 to AR, indicating that PRNCR1 is required for PCGEM recruitment. Depletion of either PRNCR1 or PCGEM1 significantly reduced canonical AR target gene expression, and the vast majority of the lncRNA binding sites colocalized with AR-bound enhancer regions, consistent with a direct role of PRNCR1 and PCGEM1 in AR-mediated transcriptional activity. PRNCR1 and PCGEM1 were also capable of binding the ligand-independent, truncated form of AR found in castration-resistant prostate cancer (CRPC) and were highly expressed in CRPC cell lines. PRNCR1 and PCGEM1 were both required for the constitutive transactivation activity of truncated AR in CRPC cells, and knockdown of either PRNCR1 or PCGEM1 significantly inhibited the proliferation of a CRPC cell line both in vitro and in vivo. Mechanistically, PRNCR1 and PCGEM1 mediated the formation of chromatin loops between AR-bound enhancers and AR target gene promoters through the interaction of PCGEM with pygopus 2, a PHD domain-containing protein that binds H3K4me3 and is required for AR target gene activation. Together, these findings point to a role for PRNCR1 and PCGEM1 in regulation of the AR transcriptional program and suggest that their overexpression may contribute to prostate cancer progression and the development of CRPC.
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