GSK3β 通过 CHIP 介导的 Slug 降解来控制上皮-间质转化和肿瘤转移。
GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.
机构信息
Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
出版信息
Oncogene. 2014 Jun 12;33(24):3172-82. doi: 10.1038/onc.2013.279. Epub 2013 Jul 15.
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
糖原合酶激酶 3β（GSK3β）在上皮性癌症中高度失活，已知其可抑制肿瘤迁移和侵袭。含锌指的转录抑制因子 Slug 抑制 E-钙黏蛋白转录并增强上皮-间充质转化（EMT）。在这项研究中，我们发现非小细胞肺癌中 GSK3β-pSer9 水平与 Slug 的表达相关。GSK3β 介导的 Slug 磷酸化促进 Slug 蛋白周转。蛋白质组学分析显示，Hsc70 相互作用蛋白（CHIP）的羧基末端与野生型 Slug（wtSlug）相互作用。CHIP 的敲低稳定了 wtSlug 蛋白并减少了 Slug 的泛素化和降解。相比之下，非磷酸化的 Slug-4SA 不会被 CHIP 降解。不可降解的 Slug 的积累可能进一步导致 E-钙黏蛋白表达的抑制，并促进癌细胞迁移、侵袭和转移。我们的研究结果提供了证据表明，一种新的 GSK3β-CHIP-Slug 途径可能参与肺癌转移的进展。
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