The Role of Alcohol-Induced Golgi Fragmentation for Androgen Receptor Signaling in Prostate Cancer
The Role of Alcohol-Induced Golgi Fragmentation for Androgen Receptor Signaling in Prostate Cancer
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DOI：
10.1158/1541-7786.mcr-18-0577
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发表时间：
2019-01-01
影响因子：
5.2
通讯作者：
Petrosyan, Armen
中科院分区：
文献类型：
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作者：
Manca, Sonia;Frisbie, Cole P.;Petrosyan, Armen
多项流行病学观察和荟萃分析清楚地表明酒精滥用与前列腺癌的发病率和进展之间存在联系;然而，其机制仍然是个谜。最近，人们发现，乙醇（EtOH）诱导的高尔基复合体的功能受损的最大的高尔基体基质蛋白，giantin（GOLGB 1），这反过来又改变了常驻高尔基体蛋白的高尔基对接造成的解体。在此，确定在正常前列腺细胞中，组蛋白脱乙酰基酶6（HDAC 6），雄激素受体（AR）信号传导的已知调节剂，定位于细胞质和细胞核中，而其激酶，糖原合成酶激酶β（GSK 3 β），主要存在于高尔基体中。前列腺癌的进展伴随着高尔基体散射、GSK 3 β从高尔基体易位到细胞质以及HDAC 6定位的细胞质移位。乙醇脱氢酶产生的代谢产物诱导雄激素反应性LNCaP和22 Rv 1细胞中的高尔基体解体，促进小鼠异种移植模型中的肿瘤生长，并激活锚定非依赖性增殖、迁移和细胞粘附。EtOH处理的细胞表现出减少的巨蛋白和随后的细胞质GSK 3 β;这种现象在巨蛋白耗尽的细胞中得到验证。GSK 3 β重新分布到细胞质导致HDAC 6磷酸化并保留在细胞质中，这反过来又刺激HSP 90的脱乙酰化、AR输入细胞核和前列腺特异性抗原（PSA）的分泌。最后，高尔基体形态，HDAC 6细胞质含量，和临床病理特征之间的关系进行了评估，在人类前列腺癌患者标本与无酒精dependence.Implications的历史：这项研究表明，在AR介导的增殖激活酒精诱导的高尔基体碎片的重要性。
Multiple epidemiologic observations and meta-analysis clearly indicate the link between alcohol abuse and the incidence and progression of prostate cancer; however, the mechanism remains enigmatic. Recently, it was found that ethanol (EtOH) induces disorganization of the Golgi complex caused by impaired function of the largest Golgi matrix protein, giantin (GOLGB1), which, in turn, alters the Golgi docking of resident Golgi proteins. Here, it is determined that in normal prostate cells, histone deacetylase 6 (HDAC6), the known regulator of androgen receptor (AR) signaling, localizes in the cytoplasm and nucleus, while its kinase, glycogen synthase kinase beta (GSK3 beta), primarily resides in the Golgi. Progression of prostate cancer is accompanied by Golgi scattering, translocation of GSK3 beta from the Golgi to the cytoplasm, and the cytoplasmic shift in HDAC6 localization. Alcohol dehydrogenase-generated metabolites induces Golgi disorganization in androgen-responsive LNCaP and 22Rv1 cells, facilitates tumor growth in a mouse xenograft model and activates anchorage-independent proliferation, migration, and cell adhesion. EtOH-treated cells demonstrate reduced giantin and subsequent cytoplasmic GSK3 beta; this phenomenon was validated in giantin-depleted cells. Redistribution of GSK3 beta to the cytoplasm results in phosphorylation of HDAC6 and its retention in the cytoplasm, which, in turn, stimulates deacetylation of HSP90, AR import into the nucleus, and secretion of prostate-specific antigen (PSA). Finally, the relationship between Golgi morphology, HDAC6 cytoplasmic content, and clinicopathologic features was assessed in human prostate cancer patient specimens with and without a history of alcohol dependence.Implications: This study demonstrates the importance of alcohol-induced Golgi fragmentation in the activation of AR-mediated proliferation.