雄激素受体 (AR) 在前列腺癌 (PCa) 进展中至关重要，是一个关键的治疗靶点。 AR介导的基因调控涉及与核蛋白的复杂相互作用，其中许多介导和经历翻译后修饰，从而提供替代治疗途径。通过 PCa 细胞中的染色质蛋白质组学，我们鉴定了 SUMO 连接酶以及 AR 蛋白质网络中的核受体共调节因子和先锋转录因子。有趣的是，该网络显示出与 SUMO2/3 的显着关联。为了阐明 SUMO 化对 AR 染色质相互作用和随后基因调控的影响，我们使用 ML-792 (SUMOi) 抑制 SUMO 化。虽然雄激素通常会促进 SUMO2/3 和 AR 在染色质上的共存，但 SUMOi 会根据 AR 结合位点 (ARB) 的类型诱导不同的效应。 SUMOi 增强了 AR 对富含雄激素反应元件 (ARE) 的不可接近染色质区域的先锋样结合，并减少了其与 ARE 中稀疏但富含先锋转录因子基序的可接近染色质区域的相互作用。 SUMOi 影响的 ARB 对 AR 调节基因的影响不同；那些与 AR 介导的激活相关的细胞在细胞增殖的负调节中发挥作用，而那些与 AR 介导的抑制相关的细胞则参与模式的形成。总之，我们的研究结果强调了 SUMOylation 在塑造 AR 在 PCa 细胞中的作用方面的普遍影响，有可能揭示新的治疗策略。© 作者 2024。由牛津大学出版社代表 Nucleic Acids Research 出版。

The androgen receptor (AR) is pivotal in prostate cancer (PCa) progression and represents a critical therapeutic target. AR-mediated gene regulation involves intricate interactions with nuclear proteins, with many mediating and undergoing post-translational modifications that present alternative therapeutic avenues. Through chromatin proteomics in PCa cells, we identified SUMO ligases together with nuclear receptor coregulators and pioneer transcription factors within the AR's protein network. Intriguingly, this network displayed a significant association with SUMO2/3. To elucidate the influence of SUMOylation on AR chromatin interactions and subsequent gene regulation, we inhibited SUMOylation using ML-792 (SUMOi). While androgens generally facilitated the co-occupancy of SUMO2/3 and AR on chromatin, SUMOi induced divergent effects dependent on the type of AR-binding site (ARB). SUMOi augmented AR's pioneer-like binding on inaccessible chromatin regions abundant in androgen response elements (AREs) and diminished its interaction with accessible chromatin regions sparse in AREs yet rich in pioneer transcription factor motifs. The SUMOi-impacted ARBs divergently influenced AR-regulated genes; those associated with AR-mediated activation played roles in negative regulation of cell proliferation, while those with AR-mediated repression were involved in pattern formation. In conclusion, our findings underscore the pervasive influence of SUMOylation in shaping AR's role in PCa cells, potentially unveiling new therapeutic strategies.© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.