The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression

Castration-resistant prostate cancer (CRPC) remains prostate cancer research and treatment bottleneck. Abnormal androgen receptor (AR) activation still has a pivotal role in CRPC. Multiple mechanisms involve the process, of which overabundant AR-V7 mRNA splicing production is currently focused and increasingly studied. However, factually, there is no definite conclusion about regulation of AR-V7 mRNA splicing. Recently developed knowledge has demonstrated that JMJD6 and U2AF65 as a hopeful approach in mRNA splicing regulation. The authors propose a novel possible mechanism elucidating AR mRNA splicing for CRPC progression using dual-function enzyme JMJD6 and its induced JMJD6/U2AF65/AR-V7 axis. In this hypothesis JMJD6 introduces to AR promoter to demethylate H3R or H4R and promotes AR mRNA transcription via its demethylase activity and interaction with U2AF65. It is expected that JMJD6 could further effectively perform U2AF65 hydroxylation to achieve AR-V7 mRNA splicing via its hydroxylase activity.