Objective To understand how SIRT1 differently regulates oncogenesis in hepatocellular carcinoma (HCC) with wild type and mutant type p53.Methods HCC cell line PLC5 cells (249 site mutated p53),and HepG2 cells (wild type p53) were infected with lentivirus containing shSIRT1.Western blotting was used for signaling pathway detection.Cell growth and proliferation assay,colony formation assay and tumor xenograft assay were performed to test the tumor growth ability of HepG2 cells,HepG2-shSIRT1 cells,PLC5 cells and PLC5-shSIRT1 cells respectively.Results SIRT1 silencing resulted in significant inhibition of cell proliferation in HepG2 cells but stimulating cell proliferation in PLC5 cells (t =3.595,P ＜0.01).Acetylation of p53 was found in HepG2 (HepG2-shSIRT1) and p21 was up-regulated,however,in PLC5 (PLC5-shSIRT1) cells,acetylation of p53 was found but p21 was not induced despite of p53 activation.Silence of SIRT1 resulted in no change of AMPK function in HepG2 cells but a lower activity of AMPK in PLC5 cells (t =4.268,P ＜ 0.01).Conclusions In HCC cell lines the function following SIRT1 activation is largely determined by p53 mutant status.