FUSE Binding Protein1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53 and p53‐Regulatory Factors

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis C (CHC), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Immunohistochemistry of archived HCC tumors showed abundant FBP expression in HCC tumors with CHC background. Oncomine data analysis of normal versus HCC tumors with CHC background indicated a 4‐fold increase in FBP expression with a concomitant 2.5‐fold decrease in the expression of p53.We found that FBP promotes HCV replication by inhibiting p53, and regulating BCCIP and TCTP, which, respectively, are positive and negative regulators of p53. The severe inhibition of HCV replication in FBP‐knockdown Huh7.5 cells was restored to a normal level by downregulation of either p53 or BCCIP. Although p53 in Huh7.5 cells is transcriptionally inactive as a result of Y220C mutation, we found that activation and DNA binding ability of Y220C p53 were strongly suppressed by FBP, but significantly activated upon knockdown of FBP. Transient expression of FBP in FBP‐knockdown cells fully restored the control phenotype in which the DNA binding ability of p53 was strongly suppressed. Using EMSA and ITC, we found no significant difference in in‐vitro target DNA binding affinity of recombinant wild‐type p53 and its Y220C mutant p53. However, in the presence of recombinant FBP, DNA binding ability of p53 is strongly inhibited. We confirmed that FBP downregulates BCCIP, p21, and p53, and upregulates TCTP under radiation‐induced stress. Since FBP is overexpressed in most HCC tumors with HCV background, it may have a role in promoting persistent virus infection and tumorigenesis.