Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation
Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation
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盐诱导激酶 (SIK1) 调节 HCC 进展和 WNT/β-连环蛋白激活
DOI：
10.1016/j.jhep.2016.01.005
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发表时间：
2016-05-01
影响因子：
25.7
通讯作者：
Zhang, Zhiyong
中科院分区：
文献类型：
--
作者：
Qu, Chao;He, De;Zhang, Zhiyong
背景与目的：在这项研究中，我们研究了盐诱导激酶 1 (SIK1) 的作用及其在人肝细胞癌 (HCC) 中的可能机制。方法：采用免疫沉淀、免疫组织化学、荧光素酶报告基因、染色质免疫沉淀、体外激酶测定和小鼠模型来检测SIK1对β-catenin信号通路的作用。结果：与正常对照相比，HCC中SIK1的表达显着下调。将其引入 HCC 细胞可显着抑制异种移植肿瘤模型中的上皮间质转化 (EMT)、肿瘤生长和肺转移。 SIK1 对肿瘤发展的影响至少部分是通过 β-catenin 的调节发生的，SIK1 过度表达会导致 β-catenin 转录活性受到抑制，而 SIK1 缺失则会产生相反的效果，这一事实就证明了这一点。从机制上讲，SIK1 在苏氨酸 (T)1391 处磷酸化视黄酸和甲状腺激素受体 (SMRT) 的沉默介体，从而促进核受体辅阻遏物 (NCoR)/SMRT 与转导蛋白-β 样蛋白 1 (TBL1)/转导-β 样 1 X 连锁受体 1 (TBLR1) 的结合，并破坏 β-连环蛋白与TBL1/TBLR1 复合物，从而使 Wnt/β-catenin 通路失活。然而，SMRT-T1391A 逆转 SIK1 表型并促进 β-连环蛋白反式激活。 Twist1 被确定为 SIK1/β-连环蛋白轴下游的关键因子，Twist1 敲低 (Twist1(KD)) 可逆转 SIK1(KD) 介导的变化，而 SIK1(KD)/Twistlic 双敲低细胞在建立肿瘤生长和转移方面的效率低于 SIK1 MD 细胞。 SIK1的启动子活性受到Twist1的负调节，表明存在双负反馈环。重要的是，SIK1 的水平与人类 HCC 标本中 Twist1 的表达呈负相关。结论：我们的研究结果强调了 SIK1 及其靶标在 HCC 发展调节中的关键作用，并为 HCC 治疗提供了潜在的新候选者。 (C) 2016 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: In this study, we investigated the role of salt-inducible kinase 1 (SIK1) and its possible mechanisms in human hepatocellular carcinoma (HCC). Methods: Immunoprecipitation, immunohistochemistry, luciferase reporter, Chromatin immunoprecipitation, in vitro kinase assays and a mouse model were used to examine the role of SIK1 on the beta-catenin signaling pathway.Results: SIK1 was significantly downregulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppresses epithelial-to-mesenchymal transition (EMT), tumor growth and lung metastasis in xenograft tumor models. The effect of SIK1 on tumor development occurs at least partially through regulation of beta-catenin, as evidenced by the fact that SIK1 overexpression leads to repression of beta-catenin transcriptional activity, while SIK1 depletion has the opposite effect. Mechanistically, SIK1 phosphorylates the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) at threonine (T)1391, which promotes the association of nuclear receptor corepressor (NCoR)/SMRT with transducin-beta-like protein 1 (TBL1)/transducing-beta-like 1 X-linked receptor 1 (TBLR1) and disrupts the binding of beta-catenin to the TBL1/TBLR1 complex, thereby inactivating the Wnt/beta-catenin pathway. However, SMRT-T1391A reverses the phenotype of SIK1 and promotes beta-catenin transactivation. Twist1 is identified as a critical factor downstream of SIK1/beta-catenin axis, and Twist1 knockdown (Twist1(KD)) reverses SIK1(KD)-mediated changes, whereas SIK1(KD)/Twistlic double knockdown cells were less efficient in establishing tumor growth and metastasis than SIK1 MD cells. The promoter activity of SIK1 were negatively regulated by Twist1, indicating that a double-negative feedback loop exists. Importantly, levels of SIK1 inversely correlate with Twist1 expression in human HCC specimens.Conclusions: Our findings highlight the critical roles of SIK1 and its targets in the regulation of HCC development and provides potential new candidates for HCC therapy. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.