Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, China.
J Cell Physiol. 2020 Mar;235(3):2129-2138. doi: 10.1002/jcp.29117. Epub 2019 Aug 29.
Castration-resistant prostate cancer (CRPC) causes most of the deaths in patients with prostate cancer (PCa). The androgen receptor (AR) axis plays an important role in castration resistance. Emerging studies showed that the lysine demethylase KDM4B is a key molecule in AR signaling and turnover, and autophagy plays an important role in CRPC. However, little is known about whether KDM4B promotes CRPC progression by regulating autophagy. Here we used an androgen-independent LNCaP (LNCaP-AI) cell line to assay aberrant KDM4B expression using qPCR and western blot analysis and investigated the function of KDM4B in regulating cell proliferation. We found that KDM4B was markedly increased in LNCaP-AI cells compared with LNCaP cells. KDM4B level was significantly correlated with the Gleason score in PCa tissues. In vitro, KDM4B overexpression in CRPC cells promoted cell proliferation, whereas knockdown of KDM4B significantly inhibited cell proliferation. Upregulated KDM4B contributed to activate Wnt/β-catenin signaling and autophagy. Moreover, KDM4B activated autophagy by regulating the Wnt/β-catenin signaling. Finally, we demonstrated that autophagy inhibition attenuated KDM4B-induced CRPC cell proliferation. Our results provided novel insights into the function of KDM4B-driven CRPC development and indicated that KDM4B may be served as a potential target for CRPC therapy.
去势抵抗性前列腺癌（CRPC）是导致前列腺癌（PCa）患者死亡的主要原因。雄激素受体（AR）轴在去势抵抗中起重要作用。新兴研究表明，赖氨酸去甲基酶 KDM4B 是 AR 信号转导和周转的关键分子，自噬在 CRPC 中起重要作用。然而，目前尚不清楚 KDM4B 是否通过调节自噬来促进 CRPC 的进展。在这里，我们使用雄激素非依赖性 LNCaP（LNCaP-AI）细胞系通过 qPCR 和 Western blot 分析检测异常 KDM4B 表达，并研究了 KDM4B 在调节细胞增殖中的功能。我们发现，与 LNCaP 细胞相比，LNCaP-AI 细胞中 KDM4B 明显增加。KDM4B 水平与 PCa 组织中的 Gleason 评分显著相关。在体外，CRPC 细胞中 KDM4B 的过表达促进了细胞增殖，而 KDM4B 的敲低则显著抑制了细胞增殖。上调的 KDM4B 有助于激活 Wnt/β-catenin 信号和自噬。此外，KDM4B 通过调节 Wnt/β-catenin 信号来激活自噬。最后，我们证明了自噬抑制减弱了 KDM4B 诱导的 CRPC 细胞增殖。我们的研究结果为 KDM4B 驱动的 CRPC 发展的功能提供了新的见解，并表明 KDM4B 可能作为 CRPC 治疗的潜在靶点。
