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.

赖氨酸 (K) 特异性脱甲基酶 6B (KDM6B) 是一种应激诱导型 H3K27me3 脱甲基酶，根据肿瘤细胞的类型在恶性肿瘤中发挥致癌或抗肿瘤作用。然而，这种组蛋白修饰剂如何影响前列腺癌 (PCa) 的进展仍然未知。在这里，我们分析了测序的基因表达数据和组织微阵列，以探索 KDM6B 在 PCa 中的表达特征和预后价值。此外，我们进行了体外细胞生物学实验和体内裸鼠模型，以揭示 KDM6B 的生物学功能、上下游调控机制。此外，我们研究了 KDM6B 抑制剂 GSK-J4 对 PCa 细胞的影响。我们发现在 PCa 中观察到 KDM6B 过表达，并且 KDM6B 表达升高与高格里森评分相关，血清前列腺特异性抗原水平低，无复发生存期短。此外，KDM6B 促进增殖、迁移、侵袭和细胞周期进程，并抑制 PCa 细胞的凋亡。GSK-J4 给药可以显着抑制 KDM6B 在 PCa 细胞中的生物学功能。KDM6B 参与去势抵抗性前列腺癌 (CRPC) 的发展，MDV3100 加 GSK-J4 的组合对 CRPC 和 MDV3100 抵抗性 CRPC 有效。机制探索揭示雄激素受体可降低KDM6B的转录，KDM6B使细胞周期蛋白D1启动子处的H3K27me3去甲基化，并与smad2/3协同促进细胞周期蛋白D1的表达。综上所述，