Hepatitis B virus X protein modulates peroxisome proliferator-activated receptor γ through protein–protein interaction

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Authors: Youn-Hee Choi ; Ha-il Kim ; Jeon Han Park ; Se Jong Kim ; Yong-ho Ahn ; Jae Myun Lee ; Mi-Ock Lee ; Hyeseong Cho ; Dae-Yeul Yu ; Je Kyung Seong

MeSH: Adenoviridae ; Apoptosis/drug effects ; Base Sequence ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/virology ; Cell Division/drug effects ; Cell Line ; DNA Primers ; Genes, Reporter ; Genetic Vectors ; Green Fluorescent Proteins ; Hepatitis B Antigens/chemistry ; Hepatitis B Antigens/pharmacology ; Humans ; Ligands ; Liver Neoplasms/pathology ; Liver Neoplasms/virology ; Luminescent Proteins/genetics ; Protein Transport/drug effects ; Receptors, Cytoplasmic and Nuclear/chemistry ; Receptors, Cytoplasmic and Nuclear/drug effects ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism* ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/drug effects ; Recombinant Fusion Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Trans-Activators/chemistry ; Trans-Activators/metabolism ; Trans-Activators/pharmacology* ; Transcription Factors/chemistry ; Transcription Factors/drug effects ; Transcription Factors/genetics ; Transcription Factors/metabolism* ; Transfection ; Tumor Cells, Cultured

Keywords: Hepatitis B virus X protein ; Peroxisome proliferator-activated receptor γ ; Transactivation ; Protein–protein interaction ; PPARγ, peroxisome proliferator-activated receptor γ ; HCC, hepatocellular carcinoma ; HBx, hepatitis B virus X protein ; HBV, hepatitis B virus ; RXR, retinoid X receptor ; PPRE, peroxisome proliferator response element ; HBx-TG, hepatitis B virus X protein transgenic ; EMSA, electrophoretic mobility shift assay ; HA, hemagglutinin ; NE, nuclear extract ; DBD, DNA binding domain ; LBD, ligand binding domain ; NLS, nuclear localization signal ; IFA, immunofluorescence assay ; rHBx, recombinant hepatitis B virus X protein

Abstract: Ligand activation of peroxisome proliferator-activated receptor γ (PPARγ) has been reported to induce growth inhibition and apoptosis in various cancers including hepatocellular carcinoma (HCC). However, the effect of hepatitis B virus X protein (HBx) on PPARγ activation has not been characterized in hepatitis B virus (HBV)-associated HCC. Herein, we demonstrated that HBx counteracted growth inhibition caused by PPARγ ligand in HBx-associated HCC cells. We found that HBx bound to DNA binding domain of PPARγ and HBx/PPARγ interaction blocked nuclear localization and binding to recognition site of PPARγ. HBx significantly suppressed a PPARγ-mediated transactivation. These results suggest that HBx modulates PPARγ function through protein–protein interaction.