Zhuang Dian, Kang Jinsong, Luo Haoge, Tian Yu, Liu Xiaoping, Shao Chen
Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
BMC Biol. 2025 Feb 28;23(1):66. doi: 10.1186/s12915-025-02172-4.
Androgen deprivation therapy (ADT) induces cellular senescence and tumor stasis, thus serving as the standard treatment for prostate cancer (PCa). However, continuous suppression of canonical androgen receptor signaling actually leads to the switch from androgen-responsive growth to androgen-independent growth, contributing to "escape" from this ADT-induced senescence (AIS) and, subsequently, the development of castration-resistant prostate cancer (CRPC). Unfortunately, the mechanism underlying this phenomenon remains elusive.
In this study, we demonstrated that androgen receptor splicing variant 7 (ARv7), a dominant factor mediating abnormal AR signaling and ADT resistance, is closely associated with outgrowth from AIS of PCa cells. Mechanistically, ARv7 binds to the promoter of SKP2, activating its transcription, and then promotes the proteasomal degradation of the cell cycle regulator p27 and G1/S transition. In addition, we applied bioinformatic and in vitro analyses to show that SKP2 expression level is dramatically inhibited upon ADT, but its reactivation is one key step during the establishment of CRPC. Finally, we also demonstrated that SKP2 inhibitor treatment can significantly inhibit the growth of androgen-independent cell lines and enhance the efficacy of ADT.
Our work reveals a novel role of ARv7 in regulating AIS and suggests that targeting the ARv7/SKP2/p27 axis could be a potential strategy to delay disease progression to the CRPC state during prolonged ADT.
雄激素剥夺疗法（ADT）可诱导细胞衰老和肿瘤停滞，因此是前列腺癌（PCa）的标准治疗方法。然而，持续抑制经典雄激素受体信号实际上会导致从雄激素依赖型生长转变为雄激素非依赖型生长，促使癌细胞从这种ADT诱导的衰老（AIS）中“逃脱”，进而导致去势抵抗性前列腺癌（CRPC）的发生。不幸的是，这一现象背后的机制仍不清楚。
在本研究中，我们证明雄激素受体剪接变体7（ARv7）作为介导异常AR信号和ADT抗性的主要因子，与PCa细胞AIS后的生长密切相关。从机制上讲，ARv7与SKP2的启动子结合，激活其转录，然后促进细胞周期调节因子p27的蛋白酶体降解和G1/S期转换。此外，我们通过生物信息学和体外分析表明，ADT后SKP2表达水平受到显著抑制，但其重新激活是CRPC形成过程中的关键步骤。最后，我们还证明SKP2抑制剂治疗可显著抑制雄激素非依赖细胞系的生长，并增强ADT的疗效。
我们的研究揭示了ARv7在调节AIS中的新作用，并表明靶向ARv7/SKP2/p27轴可能是一种在长期ADT期间延缓疾病进展至CRPC状态的潜在策略。
