A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance
A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance
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DOI：
10.1038/s41388-021-01851-0
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发表时间：
2021-06-02
期刊：
影响因子：
8
通讯作者：
Huang, Hongbiao
中科院分区：
文献类型：
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作者：
Liao, Yuning;Liu, Yuan;Huang, Hongbiao
前列腺癌（PC）是男性中第二大最常见的癌症，治疗选择有限。虽然胚胎信号在成体细胞中的重新激活是癌症的特征之一，但潜在的蛋白质降解机制仍然难以捉摸。在这里，我们表明，分子伴侣GRP 75是PC细胞中的一个关键球员，通过保持蛋白质的稳定性SIX 1，胚胎发育的转录因子。从机制上讲，GRP 75提供了一个平台来招募去泛素化酶USP 1，以抑制SIX 1的K48连接的多聚泛素化。在结构上，GRP 75的C-末端（433-679 aa）含有肽结合结构域，其是形成GRP 75-USP 1-SIX 1蛋白复合物所必需的。GRP 75-USP 1-SIX 1蛋白复合物的功能性、药理学或遗传抑制抑制肿瘤生长，并克服体外和异种移植小鼠模型中PC细胞的去势抗性。临床上，SIX 1蛋白在PC肿瘤组织中的表达与GRP 75和USP 1的表达呈正相关。这些新发现不仅加深了我们对蛋白质降解机制的理解，而且可能为增强雄激素抑制治疗的抗癌活性提供潜在的途径。
Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.