Ji Fu-Hao, Qian Yu-Hang, Guo Xiu-Chen, Liao Hai-Hong, Huang Jia-Cheng, Xu Zi-Han, Yu Ming-Ming, Wu Yan-Yuan, Bao Jie-Wen, Chen Hao-Jie, Yu Yong-Jiang, Wang Lin
Department of Urology, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, People's Republic of China.
Department of Urology, School of Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China.
Biomark Res. 2025 Aug 23;13(1):109. doi: 10.1186/s40364-025-00822-x.
The androgen receptor signaling inhibitor enzalutamide (Enz) is one the primary therapeutic drugs for advanced prostate cancer (PCa). Nevertheless, most of patients ultimately develop resistance to Enz. Through an integrated analysis of CRISPR genome-wide and kinome-wide screens, coupled with observations of elevated expression levels in Enz-resistant cell lines and PCa tumor tissues, our study identified RPS6KC1 as a novel essential gene implicated in Enz resistance. Mechanistically, our research indicates that the Warburg effect induces H3K18 lactylation, which regulates the expression of RPS6KC1 via the transcription factor P65. Elevated expression of RPS6KC1 was found to recruit PRDX3 to the mitochondria, thereby mitigating ferroptosis. These findings suggest that the H3K18la/NF-κB/RPS6KC1/PRDX3 axis is important for the development of resistance to Enz. Our results suggest that the combination of Enz with targeted RPS6KC1 inhibition or a ferroptosis inducer may represent a promising therapeutic strategy to overcome Enz resistance.
雄激素受体信号抑制剂恩杂鲁胺（Enz）是晚期前列腺癌（PCa）的主要治疗药物之一。然而，大多数患者最终会对Enz产生耐药性。通过对CRISPR全基因组和全激酶组筛选的综合分析，结合对Enz耐药细胞系和PCa肿瘤组织中表达水平升高的观察，我们的研究确定RPS6KC1是一个与Enz耐药相关的新的必需基因。从机制上讲，我们的研究表明，瓦伯格效应诱导H3K18乳酸化，其通过转录因子P65调节RPS6KC1的表达。发现RPS6KC1的表达升高会将PRDX3募集到线粒体，从而减轻铁死亡。这些发现表明，H3K18la/NF-κB/RPS6KC1/PRDX3轴对Enz耐药的发展很重要。我们的结果表明，Enz与靶向RPS6KC1抑制或铁死亡诱导剂联合使用可能是克服Enz耐药的一种有前景的治疗策略。
