PCAT1 Supports Partial AR-V7 Function and Promotes Enzalutamide Resistance in Prostate Cancer

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

Background Enzalutamide resistance (Enz-R) remains a major clinical challenge in advanced prostate cancer (PCa). Here, we identified resistance-associated long non-coding RNA (lncRNA) PCAT1 and investigated its functional relevance in Enz-R PCa. Methods Public transcriptomic datasets, bioinformatic analyses, RNA immunoprecipitation (RIP), ChIP-qPCR, and in vitro and in vivo functional assays were used to evaluate the expression, function, and potential mechanism of PCAT1 in Enz-R PCa models. Results PCAT1 was upregulated in Enz-R PCa models and was associated with adverse clinical features. PCAT1 knockdown inhibited the growth of C4-2 Enz-R cells and 22Rv1 cells and suppressed tumor growth in vivo. Mechanistically, PCAT1 was associated with AR/AR-V7 and supported selected AR-V7-associated downstream outputs without markedly altering AR-V7 protein expression. AR-V7 ChIP-qPCR further suggested that PCAT1 knockdown reduced AR-V7 enrichment at selected regulatory regions, including the KLK3 and PMEPA1 enhancers. In addition, high-dose androgen treatment reduced PCAT1 and AR-V7 expression in our experimental model. Conclusion PCAT1 contributes to Enz-R PCa growth and may support selected AR-V7-associated transcriptional outputs. PCAT1 may represent a potential therapeutic vulnerability, and the relationship between high-dose androgen treatment, PCAT1 suppression, and AR-V7 signaling warrants further investigation.