Department of Urology, Tongji Hospital, Tongji University, Shanghai 200065, China.
Department of Urology, Tongji Hospital, Tongji University, Shanghai 200065, China.
Biomed Pharmacother. 2019 Jun;114:108793. doi: 10.1016/j.biopha.2019.108793. Epub 2019 Mar 25.
Prostate cancer (PCa) is one of the leading causes of cancer-related death worldwide, and it is almost incurable once it has developed into castration-resistance prostate cancer (CRPC). However, the mechanisms underlying the oncogenesis of PCa and CRPC remain elusive. Lysine-specific histone demethylase 5C (KDM5C) is an important member of lysine demethylase family and has recently been found highly expressed in multiple cancer types. In this study, we reported that KDM5C was highly expressed in PCa and CRPC specimens, and the high expression promoted CRPC cell proliferation through repressing phosphatase and tensin homolog (PTEN) gene epigenetically. Moreover, KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. Taken together, our study uncovers that the BRD4-KDM5C-PTEN may be a new oncogenic pathway in CRPC development, and KDM5C is a critical protein and could be an ideal target for CRPC treatment in this oncogenic pathway.
前列腺癌（PCa）是全球癌症相关死亡的主要原因之一，一旦发展为去势抵抗性前列腺癌（CRPC），几乎无法治愈。然而，PCa 和 CRPC 发生的机制仍难以捉摸。赖氨酸特异性组蛋白去甲基化酶 5C（KDM5C）是赖氨酸去甲基化酶家族的重要成员，最近在多种癌症类型中发现其高表达。在这项研究中，我们报道 KDM5C 在 PCa 和 CRPC 标本中高度表达，并且其高表达通过表观遗传抑制磷酸酶和张力蛋白同源物（PTEN）基因促进 CRPC 细胞增殖。此外，KDM5C 被溴结构域蛋白 4（BRD4）转录上调，敲低 KDM5C 可使 CRPC 细胞对溴结构域和末端（BET）抑制剂的治疗效果敏感。总之，我们的研究揭示了 BRD4-KDM5C-PTEN 可能是 CRPC 发展中的新致癌途径，KDM5C 是一个关键蛋白，并且可能是该致癌途径中 CRPC 治疗的理想靶点。
