Hepatitis B virus (HBV) is a causative agent of chronic hepatitis and hepatocellular carcinoma. Recent findings demonstrating p73 and specifically N-terminally truncated p73 (DeltaTAp73) accumulation in hepatocellular carcinoma suggest that p73 plays a role in the malignant phenotype. Here, we investigated the mechanism of HBV pregenomic core promoter/enhancer II (cp/EII) regulation by full-length TAp73 and its oncogenic counterpart DeltaTAp73. Ectopic and endogenous expression of TAp73 leads to a significant downregulation of cp/EII activity in p53-deficient hepatoma cell lines. In contrast, overexpression of DeltaTAp73 results in significant cp/EII activation and increased HBV core (HBc) expression. TAp73-mediated repression of HBV transcription was substantially abolished by DeltaTAp73. We show that both TAp73 and DeltaTAp73 proteins directly bind to the Sp1 transcription factor, a key stimulator of HBV gene expression. However, only TAp73 abolishes Sp1 binding to cp/EII, whereas the DeltaTAp73-Sp1 complex further persists on the DNA. The inhibitory effect of p53/p73 on HBc expression is associated with the inhibition of viral replication, while DeltaTAp73 is not. These data strongly support the fact that the p73-isoform-related interaction with Sp1 is the underlying mechanism of the diverse outcome on HBc expression, suggesting a new mechanism by which oncogenic DeltaTAp73 could enhance the carcinogenic process in liver cells.
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