Chukhu Muj, Dahiya Ujjwal R, Heemers Hannelore V
Department of Cancer Biology, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA.
Oncogene. 2025 Sep 18. doi: 10.1038/s41388-025-03573-z.
The androgen receptor (AR) is a ligand-activated transcription factor that is a major driver of lethal prostate cancer (CaP) progression. Androgen deprivation therapy (ADT) that prevents the binding of androgens to AR has been the mainstay for the treatment of non-organ-confined CaP for more than 8 decades. Although ADT initially induces remissions, eventually resistance occurs while the majority of castration-resistant CaPs (CRPCs) continue to rely on AR's action for growth. Sustained AR-dependence of CaP that recurs under ADT has historically been linked to AR's transcriptional activity that controls expression of a distinct program of target genes that mediate aggressive behavior. Recently, less traditional transcriptional roles for AR, such as those impacting non-coding RNAs as well as transcription-independent roles that include AR-dependent splicing programs and translation control have been recognized to contribute to aggressive CaP features and treatment resistance. We reviewed and contrasted the contribution and relevance of these distinct functions for AR during CaP progression. We also considered the roles therein, both overlapping or mutually exclusive, for functionally diverse AR-interacting proteins that have been identified and to date have been mostly considered AR-associated transcriptional regulators. We discuss the potential implications of the involvement of AR interactors in multiple AR-dependent (non-)transcriptional cellular processes for alternative CaP treatment strategies that disrupt AR-coregulator interplay to inhibit AR-dependent transcription when AR ligand-deprivation has failed.
雄激素受体（AR）是一种配体激活的转录因子，是致命性前列腺癌（CaP）进展的主要驱动因素。阻止雄激素与AR结合的雄激素剥夺疗法（ADT）八十多年来一直是治疗非器官局限性CaP的主要方法。尽管ADT最初能诱导缓解，但最终会产生耐药性，而大多数去势抵抗性CaP（CRPC）继续依赖AR的作用来生长。在ADT下复发的CaP对AR的持续依赖性在历史上一直与AR的转录活性有关，AR的转录活性控制着介导侵袭性行为的一组独特靶基因的表达。最近，人们认识到AR的一些不太传统的转录作用，如影响非编码RNA的作用，以及包括AR依赖性剪接程序和翻译控制在内的非转录作用，都有助于CaP的侵袭性特征和治疗耐药性。我们回顾并对比了CaP进展过程中AR这些不同功能的贡献和相关性。我们还考虑了已鉴定的功能多样的AR相互作用蛋白在其中的作用，这些作用既有重叠的也有相互排斥的，并且迄今为止大多被认为是AR相关的转录调节因子。我们讨论了AR相互作用因子参与多种AR依赖性（非）转录细胞过程对替代CaP治疗策略的潜在影响，当AR配体剥夺失败时，这些策略可破坏AR-共调节因子的相互作用以抑制AR依赖性转录。
