SIK2 represses AKT/GSK3β/β‐catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases

• Published in: Molecular oncology 2021-01, Vol.15 (1), p.228-245
• Main Authors: Dai, Xiao‐man, Zhang, Yan‐hui, Lin, Xiao‐han, Huang, Xiao‐xing, Zhang, Yi, Xue, Chao‐rong, Chen, Wan‐nan, Ye, Jian‐xin, Lin, Xin‐jian, Lin, Xu
• Format: Article
• Language: English
• Subjects: AKT protein; AKT/GSK3β/β‐catenin signaling; Animals; Antibodies; Autophagy; beta Catenin - metabolism; Carcinogenesis; Catenin; Cell adhesion & migration; Cell Line, Tumor; Chemotherapy; Cloning; Cohort Studies; Dephosphorylation; Down-Regulation - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Kinases; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Medical prognosis; Mesenchyme; Metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Models, Biological; Phenotype; Phenotypes; Phosphatase; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Plasmids; Prognosis; Protein Phosphatase 2 - metabolism; protein phosphatases; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Proteolysis; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; SIK2; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Therapeutic applications; Tumor suppressor genes; Tumorigenesis; Up-Regulation - genetics
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12838

Salt‐inducible kinase 2 (SIK2) functions as a tumor suppressor in gastric cancer (GC). Activation of mTORC1 by SIK2 inhibits autophagic degradation of the PP2A and PHLPP2 protein phosphatases, thereby increasing dephosphorylation and inactivation of AKT/GSK3β/β‐catenin signaling. Our results highlight SIK2 as a potential therapeutic target in GC. Salt‐inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial–mesenchymal transition via inhibition of AKT/GSK3β/β‐catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3β/β‐catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.