Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation
Abstract
In this study, we investigated the role of salt-inducible kinase 1 (SIK1) and its possible mechanisms in human hepatocellular carcinoma (HCC). Immunoprecipitation, immunohistochemistry, luciferase reporter, Chromatin immunoprecipitation, in vitro kinase assays and a mouse model were used to examine the role of SIK1 on the β-catenin signaling pathway. 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 β-catenin, as evidenced by the fact that SIK1 overexpression leads to repression of β-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 β-catenin to the TBL1/TBLR1 complex, thereby inactivating the Wnt/β-catenin pa...Continue Reading
References
Wnt5a controls Notch1 signaling through CaMKII-mediated degradation of the SMRT corepressor protein.
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