title: Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation.
abstract: OBJECTIVE
  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 β-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 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 pathway. However, SMRT-T1391A reverses the phenotype of SIK1 and promotes β-catenin transactivation. Twist1 is identified as a critical factor downstream of SIK1/β-catenin axis, and Twist1 knockdown (Twist1(KD)) reverses SIK1(KD)-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 provides potential new candidates for HCC therapy.
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of General Surgery, Affiliated Baoan Hospital of Southern Medical University, Shenzhen, China.
authors.forename: De
authors.lastname: He
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yuekun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Chang
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Xinping
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Lizhe
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Bi
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Jian
authors.initials: J
authors.lastname: He
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Medicine, College of Clinical Science, Three Gorges University, Yichang, Hubei, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Sufang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China. Electronic address: quyaqin52@163.com.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Qu
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China. Electronic address: yongxiang_zhao@126.com.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research)Guangxi Medical University, Nanning, Guangxi, China; Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, The State University of New Jersey, New Brunswick, NJ, USA. Electronic address: zhangz2@rwjms.rutgers.edu.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C495376:Sik1 protein, mouse
keywords: Epithelial-mesenchymal transition; Salt-inducible kinase 1; Silencing mediator for retinoid; Thyroid receptors; Twist1; β-catenin