SKP2 Promotes Hepatocellular Carcinoma Progression Through Inhibition Of Nuclear AMPK-SKP2-CARM1 Signaling Regulated Autophagy Induction

Background:SKP2 promotes tumor progression and its overexpression has been associated with poor prognosis in numerous cancers.The mechanisms of autophagy in the tumor pathogenesis have been a research focus recently.How the SKP2 involved in autophagy expresses oncogenic characteristics,especially in HCC,are largely unclear.Methods:The expression of SKP2 in HCC tumor tissues and HCC cell lines was detected by qPCR,Western-blot,Immunohistochemical(IHC)and Immunofluorescence(IF)techniques.SKP2 was knocked down or overexpressed by lentivirus transfection in HCC cells.Functional assays such as CCK8 assays,transwell migration and invasion assays,and colony formation assays were performed to determine the role of SKP2 in HCC.Furthermore,autophagy was induced by glucose deprivation in HCC cells followed by monitoring the levels and distributions of SKP2,CARM1 and AMPK.Results:Our data showed that SKP2 levels were significantly increased in HCC cell lines and HCC tissues rather than corresponding normal liver tissues,and augmented SKP2 levels were statistically correlated with tumor grade,size and metastases.By up-regulation or down-regulation of SKP2 in HCC cells,we confirmed that SKP2 encourages proliferation,migration and invasion.We then found that when SKP2 was inhibited,CARM1 increased and AMPKa2 became activated in the nucleus under glucose deprivation induced autophagy.Moreover,we discovered that SKP2 was repressing CARM1 in the nucleus under nutrient-sufficient conditions in HCC.Conclusions:We show that SKP2 is important for HCC tumor growth and the nuclear AMPK-SKP2-CARM1 signaling of autophagy induction participates in the progression of HCC,which offering a potential target for HCC therapy.