Ege University, Faculty of Pharmacy, Biochemistry Department, Izmir, 35100 Turkey.
Sci Rep. 2017 Jan 16;7:40719. doi: 10.1038/srep40719.
The endoplasmic reticulum (ER) comprises thirty percent of the newly translated proteins in eukaryotic cells. The quality control mechanism within the ER distinguishes between properly and improperly folded proteins and ensures that unwanted proteins are retained in the ER and subsequently degraded through ER-associated degradation (ERAD). Besides cleaning of misfolded proteins ERAD is also important for physiological processes by regulating the abundance of normal proteins of the ER. Thus it is important to unreveal the regulation patterns of ERAD. Here, we describe that ERAD pathway is regulated by androgen, where its inhibitor SVIP was downregulated, all other ERAD genes were upregulated. Consistently, androgen treatment increased the degradation rate of ERAD substrates. Using several independent techniques, we showed that this regulation is through androgen receptor transactivation. ERAD genes found to be upregulated in prostate cancer tissues and silencing expression of Hrd1, SVIP, and gp78 reduced the in vitro migration and malignant transformation of LNCaP cells. Our data suggests that expression levels of ERAD components are regulated by androgens, that promotes ERAD proteolytic activity, which is positively related with prostate tumorigenesis.
内质网（ER）包含真核细胞中新翻译的蛋白质的百分之三十。内质网内的质量控制机制区分正确折叠的蛋白质和错误折叠的蛋白质，并确保不需要的蛋白质保留在 ER 中，随后通过内质网相关降解（ERAD）降解。除了清除错误折叠的蛋白质，ERAD 对于通过调节 ER 中正常蛋白质的丰度来调节生理过程也很重要。因此，揭示 ERAD 的调节模式很重要。在这里，我们描述 ERAD 途径受雄激素调节，其抑制剂 SVIP 下调，所有其他 ERAD 基因上调。一致地，雄激素处理增加了 ERAD 底物的降解速率。使用几种独立的技术，我们表明这种调节是通过雄激素受体的反式激活。在前列腺癌组织中发现上调的 ERAD 基因，沉默 Hrd1、SVIP 和 gp78 的表达，降低了 LNCaP 细胞的体外迁移和恶性转化。我们的数据表明，ERAD 成分的表达水平受雄激素调节，促进 ERAD 蛋白水解活性，这与前列腺肿瘤发生呈正相关。
