Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer
Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer
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DOI：
10.1038/onc.2015.214
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发表时间：
2016-03-24
期刊：
影响因子：
8
通讯作者：
Su, J-L
中科院分区：
文献类型：
--
作者：
Chang, Y-W;Tseng, C-F;Su, J-L
热休克蛋白5（HSPA 5）是乳腺癌患者预后不良的标志物，在癌症进展中起重要作用，包括促进耐药性和转移。在这项研究中，我们确定，特定的赖氨酸残基447（K447）的HSPA 5可以修饰与多聚泛素随后降解通过泛素蛋白酶体系统，导致抑制细胞迁移和乳腺癌的侵袭。我们进一步发现，GP 78，一种E3泛素连接酶，与HSPA 5的C-末端区域相互作用并介导HSPA 5泛素化和降解。GP 78的敲低显著增加了HSPA 5的表达，增强了乳腺癌细胞的迁移/侵袭能力。敲低组蛋白去乙酰化酶-6（HDAC 6）可增加HSPA 5在赖氨酸残基353（K353）的乙酰化，减少GP 78介导的HSPA 5在K447的泛素化，从而增加细胞的迁移/侵袭。此外，我们证明，E3泛素连接酶GP 78优先结合脱乙酰化的HSPA 5。值得注意的是，在乳腺癌患者中GP 78的表达水平与HSPA 5水平呈负相关。GP 78低表达的患者与乳腺癌的侵袭性、晚期肿瘤分期和不良临床结局显著相关。综上所述，我们的研究结果提供了新的机制的理解，即HDAC 6促进GP 78介导的HSPA 5泛素化的HSPA 5的脱乙酰化，并表明HSPA 5蛋白的翻译后调节是至关重要的HSPA 5介导的乳腺癌转移特性。
Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.