HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer
HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer
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DOI：
10.1210/me.2009-0188
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发表时间：
2009-12-01
影响因子：
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通讯作者：
Wang, Zhou
中科院分区：
文献类型：
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作者：
Ai, Junkui;Wang, Yujuan;Wang, Zhou
castration抗性前列腺癌（PCA）的发展要求在cast割条件下，雄激素受体（AR）保持活跃，因此保持核。热休克蛋白90（HSP90）在雄激素诱导的和非依赖性的核定位和AR激活中起关键作用。组蛋白脱乙酰基酶6（HDAC6）与通过调节HSP90乙酰化来调节AR活性有关，但尚未证明。在这里，我们报告说，使用短发夹RNA在不存在或存在二氢睾丸激素（DHT）的情况下，使用短发夹RNA敲低HDAC6在内源性AR的非配体无关核定位，并抑制PSA表达和细胞生长。 SHHDAC6移动DHT刺激的C4-2集菌菌落形成的剂量反应曲线，因此需要DHT浓度高约10倍，表明对AR超敏性中的HDAC6的要求。 HDAC6敲低还抑制了c4-2的c4-2异种移植肿瘤在cast骨中的肿瘤建立，但在睾丸直立的裸鼠中不抑制。使用HDAC6缺陷型小鼠胚胎成纤维细胞的研究表明，可以通过表达脱乙酰基化模拟HSP90突变体来减轻HDAC6敲低抑制AR核定位。综上所述，我们的研究表明，HDAC6主要通过调节HSP90乙酰化来调节AR超敏反应和核定位。单独靶向HDAC6或与其他治疗方法结合使用是预防和/或治疗castration耐药性PCA的新策略。 （分子内分泌学23：1963-1972，2009）
The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa. (Molecular Endocrinology 23: 1963-1972, 2009)