Salt-Inducible Kinase 1 Absence Impairs NCoR-SMRT/TBL1-TBLR1 Interaction And Promotes Hepatocellular Carcinoma Progression

Background & Aims:In this study, we investigated the role of Salt-inducible kinase 1(SIK1) and the possible mechanisms in human hepatocellular carcinoma(HCC).Methods:Immunoprecipitation, immunohistochemistry, luciferase reporter,Chromatin-immunoprecipitation, in vitro kinase assays and mice model were used to examine the role of SIK1 on ?--catenin signalling 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?-catenin, as evidenced by the fact that SIK1 overexpression leads to repression of?-catenin transcriptional activity, while SIK1 depletion has the opposite effect.Mechanistically, SIK1 phosphorylates SMRT at T1391, which promotes the association of NCo R/SMRT with TBL1/TBLR1 and disrupts the binding of ?-catenin to TBL1/TBLR1 complex, thereby inactivating the WNT/?-catenin pathway.However, SMRT-T1391 A reverses the phenotype of SIK1 and promotes ?-catenin transactivation. Twist1 is identified as a critical factor downstream of SIK1/?-catenin axis, and Twist1 knockdown(Twist1KD) reverses SIK1KD-mediated changes,whereas SIK1 KD / Twist1 KD double knockdown cells were less efficient in establishing tumor growth and metastasis than SIK1 KD 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 provide potential new candidates for HCC therapy.