Hepatitis B virus (HBV) is a causative agent of chronic hepatitis and hepatocellular carcinoma (HCC). Recent findings demonstrating p73 and specifically N-terminally truncated p73 (deltaTAp73) accumulation in HCC 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. But 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 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.