Abstract
Liver cancer is the second frequent cause of cancer death worldwide. About 70-80% of liver cancer belongs to hepatocellular carcinoma (HCC) and nearly 60% of HCC are associated chronic hepatitis B virus (HBV) infection. HBV large surface antigen (LHBs) has been considered as a potential oncoprotein in hepatocarcinogenesis. In this study, we found that the presence of LHBs down-regulates tumor suppressor p53 in hepatocytes. This down-regulation is associated with decreased stability of p53 and increased Mdm2 expression. We also found that p53 down-regulation accompanies with intrinsic DNA damages and reduced of DNA damage response in hepatocytes. Chemical induced DNA damages fails to activate p53 and its downstream p21 in LHBs-expressing cells. Moreover, we detected a significant increase in multinucleation in LHBs-expressing cells, indicating a loss of ploidy control. The disruption of p53-Mdm2 interaction with Nutlin-3 is not sufficient to restore p53 expression in LHBs-expressing cells, whereas the inhibition of Sirtuin-mediated p53 deacetylation successfully rescues p53 expression and its biological function. To clarify how does LHBs regulates p53 stability, we identified BAG family molecular chaperone regulator 2 (Bag2), a binding partner of LHBs which acts as a chaperon protein of p53. Overexpression of Bag2 partially restored p53 expression level in LHBs-expressing cells. Together these results indicate that LHBs attenuates p53 functionality via two independent mechanisms, compete with p53 for binding to chaperon protein Bag2 and inactivate p53 by deacetylation. These findings therefore highlight the pathologic function of LHBs in HBV-mediated hepatocarcinogenesis.