Department of Urology, Tianjin Institute of Urology, The second hospital of Tianjin Medical University, Tianjin, China.
Department of Pediatric Surgery, Huai'an Maternal and Children Health Hospital, Huai'an, China.
Cell Death Dis. 2022 Nov 5;13(11):927. doi: 10.1038/s41419-022-05366-8.
Androgen receptor (AR) plays an important role in the progression of prostate cancer and has been targeted by castration or AR-antagonists. The emergence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) is inevitable. However, it is not entirely clear how ADT fails or how it causes resistance. Through analysis of RNA-seq data, we nominate ARHGEF2 as a pivotal androgen-repressed gene. We show that ARHGEF2 is directly suppressed by androgen/AR. AR occupies the enhancer and communicates with the promoter region of ARHGEF2. Functionally, ARHGEF2 is important for the growth, lethal phenotype, and survival of CRPC cells and tumor xenografts. Correspondingly, AR inhibition or AR antagonist treatment can restore ARHGEF2 expression, thereby allowing prostate cancer cells to induce treatment resistance and tolerance. Overall, our findings provide an explanation for the contradictory clinical results that ADT resistance may be caused by the up-regulation of ARHGEF2 and provide a novel target.
雄激素受体（AR）在前列腺癌的进展中起着重要作用，已经成为去势或 AR 拮抗剂的作用靶点。雄激素剥夺治疗（ADT）后出现去势抵抗性前列腺癌（CRPC）是不可避免的。然而，ADT 如何失效以及导致耐药的确切机制尚不完全清楚。通过 RNA-seq 数据分析，我们提名 ARHGEF2 为一个关键的雄激素受抑制基因。我们发现 ARHGEF2 直接受到雄激素/AR 的抑制。AR 占据增强子并与 ARHGEF2 的启动子区域通讯。功能上，ARHGEF2 对于 CRPC 细胞和肿瘤异种移植物的生长、致死表型和存活至关重要。相应地，AR 抑制或 AR 拮抗剂治疗可以恢复 ARHGEF2 的表达，从而使前列腺癌细胞诱导治疗抵抗和耐受。总的来说，我们的研究结果为 ADT 耐药可能是由于 ARHGEF2 的上调引起的这一矛盾的临床结果提供了一个解释，并为新的治疗靶点提供了依据。
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