Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant
tumors depending on the type of
tumor cell. However, how this
histone modifier affects the progression of
prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor,
GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum
prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells.
GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of
castration-resistant
prostate cancer (CRPC), and combination of
MDV3100 plus
GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that
androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the
cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of
cyclin D1. In conclusion, our study demonstrates that KDM6B is an
androgen receptor regulated gene and plays oncogenic roles by promoting
cyclin D1 transcription in PCa and
GSK-J4 has the potential to be a promising agent for the treatment of PCa.