The Effect Of Elongator On Tumor Invasion And Metastasis And DNA Repair In Hepatocellular Carcinoma

Elongator is a highly conserved multi-subunits complex.Elp3 is a core subunit.Many reports provided evidences for a physiologically important role of Elongator complex in different cellular activities.We explored the mechanism of carcinogensis of Elongator complex in two parts.Part one: The effect of Elongator Expression on Tumor Invasion and Metastasis in hepatocellular carcinoma(HCC).In this study,we investigate that overexpression and depletion of Elp3 could affect cell migration and invasion,and explore the mechanism of Elp3 in regulating the ability of cell migration and invasion.We showed that overexpression of Elp3 or Elp4 promoted the migration and invasion of HCC cells,while silencing of either one gene effectively suppressed them.We found that Elongator promoted the expression of matrix metalloproteinase-2(MMP-2)and MMP-9 by increasing phosphorylation of AKT.Intriguingly,depletion of Elp3 also inhibits the phosphorylation of AKT induced by EGF and HGF.Importantly,in vivo assay of lung metastasis in mice demonstrated that overexpression of Elp3 increased tumor nodules metastatic to lung.We also showed that Elp3 was up-regulated in HCC samples,and its expression was significantly associated with the phosphorylation of AKT.Our work provides a biochemical explanation for the migratory effect of Elongator in HCC.Part two: Elongator complex play a key role in DNA damage induced by ionizing radiation in hepatocellular carcinoma.In this study,we investigate that overexpression and depletion of Elp3 could affect DNA damage repair,and explore the mechanism of Elp3 in regulating DNA repair.We showed that overexpression of Elp3 promoted the DNA repair in HCC cells,while silencing expression effectively suppressed them.However,overexpression or depletion of Elp3 could not affect DNA repair in normal hepatocyte.We found that Elongator translocate into nuclear after DNA breaks.Subsequently combine with ATM and maintain a high degree of ATM phosphorylation and promote the increase of the phosphorylation time of ATM.We also found that Elp3 is the target gene of ATM.Once the ATM signal is activated,the expression of Elp3 protein is up-regulated.The expression of Elp3 is also increased in normal hepatocyte after DNA breaks.But Elp3 could not translocate into nuclear to bind to ATM.Thus,Elongator could not affect DNA repair in normal hepatocyte.Though this mechanism,Elongator significantly accelerate the DNA damage repair in HCC.These results explain basically how Elongator promotes DNA double strand break repair,and provide basis for overcoming radio-resistance in clinic.