Wen Simeng, Niu Yuanjie, Huang Haojie
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, China.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, USA.
Asian J Urol. 2020 Jul;7(3):203-218. doi: 10.1016/j.ajur.2019.11.001. Epub 2019 Nov 20.
Prostate cancer (PCa) is the most commonly diagnosed cancer among men in western countries. Androgen receptor (AR) signaling plays key roles in the development of PCa. Androgen deprivation therapy (ADT) remains the standard therapy for advanced PCa. In addition to its ligand androgen, accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa, especially in castration resistant prostate cancer (CRPC). To date, a number of posttranscriptional modifications of AR have been identified, including phosphorylation ( by CDK1), acetylation ( by p300 and recognized by BRD4), methylation ( by EZH2), ubiquitination ( by SPOP), and SUMOylation ( by PIAS1). These modifications are essential for the maintenance of protein stability, nuclear localization and transcriptional activity of AR. This review summarizes posttranslational modifications that influence androgen-dependent and -independent activities of AR, PCa progression and therapy resistance. We further emphasize that in addition to androgen, posttranslational modification is another important way to regulate AR activity, suggesting that targeting AR posttranslational modifications, such as proteolysis targeting chimeras (PROTACs) of AR, represents a potential and promising alternate for effective treatment of CRPC. Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.
前列腺癌（PCa）是西方国家男性中最常被诊断出的癌症。雄激素受体（AR）信号传导在PCa的发展中起关键作用。雄激素剥夺疗法（ADT）仍然是晚期PCa的标准疗法。除了其配体雄激素外，越来越多的证据表明，转录后修饰是PCa进展过程中调节AR活性的另一个重要机制，尤其是在去势抵抗性前列腺癌（CRPC）中。迄今为止，已鉴定出多种AR的转录后修饰，包括磷酸化（由CDK1介导）、乙酰化（由p300介导并被BRD4识别）、甲基化（由EZH2介导）、泛素化（由SPOP介导）和SUMO化（由PIAS1介导）。这些修饰对于维持AR的蛋白质稳定性、核定位和转录活性至关重要。本综述总结了影响AR雄激素依赖性和非依赖性活性、PCa进展和治疗抵抗的翻译后修饰。我们进一步强调，除雄激素外，翻译后修饰是调节AR活性的另一种重要方式，这表明靶向AR翻译后修饰，如AR的蛋白酶靶向嵌合体（PROTAC），代表了有效治疗CRPC的一种潜在且有前景的替代方法。还讨论了未来在AR翻译后修饰领域有待研究的潜在领域。
