Roles of KHDRBS2 and KHDRBS3 in prostate cancer progression and AR-V7 regulation

To investigate the biological functions of KHDRBS2 and KHDRBS3 in prostate cancer (PCa) progression and their potential roles in regulating androgen receptor splice variant 7 (AR-V7) expression, a key factor in castration-resistant prostate cancer (CRPC).

We performed a comprehensive analysis of publicly available datasets to examine the expression patterns of KHDRBS family members in PCa, including CRPC and neuroendocrine subtypes. In vitro experiments were conducted using AR-positive 22RV1 and AR-negative PC3 cell lines to assess the expression and regulatory interactions of KHDRBS2 and KHDRBS3. Functional assays evaluated their effects on cell proliferation and tumor growth in vivo. Additionally, KHDRBS2 protein levels were manipulated in 22RV1 cells to assess their impact on AR-V7 and full-length AR expression.

Our dataset analysis revealed distinct expression patterns of KHDRBS2 and KHDRBS3, with higher alteration frequencies in CRPC and neuroendocrine PCa. In vitro, KHDRBS2 and KHDRBS3 exhibited mutually exclusive expression, with KHDRBS2 predominantly found in AR-positive 22RV1 cells and KHDRBS3 in AR-negative PC3 cells. Reciprocal regulation between the two proteins was observed in both cell lines. Functional studies showed that both KHDRBS2 and KHDRBS3 promoted cell proliferation and tumor growth. Notably, silencing KHDRBS2 in 22RV1 cells led to a selective reduction in AR-V7 expression, without affecting full-length AR levels.

These findings uncover novel roles for KHDRBS2 and KHDRBS3 in PCa progression, with KHDRBS2 identified as a potential key regulator of AR-V7 expression. Our results provide new insights into AR splice variant regulation and highlight potential therapeutic targets for PCa treatment.