The loss of hepatitis B virus receptor NTCP/SLC10A1 in human liver cancer cells is due to epigenetic silencing

HBV is a hepatotropic virus that infects human hepatocytes expressing the viral receptor hNTCP. Without effective antiviral therapy, chronic HBV infection poses a high risk of liver cancer. However, most liver cancer cell lines, including HepG2 and Huh7, do not support HBV infection due to the absence of hNTCP expression, and the mechanism underlying this defect remains unclear. This study demonstrates a significant reduction of hNTCP in hepatocellular carcinoma samples and HepG2 cells compared to normal liver tissues and primary human hepatocytes. Despite identical h<i>NTCP</i> genetic sequences, epigenetic analyses revealed a loss of the activating histone modification H3K27ac near the h<i>NTCP</i> transcription start site in cancer cells. Treatment with histone deacetylase inhibitors restored H3K27ac levels, reactivated h<i>NTCP</i> expression, and rendered HepG2 cells susceptible to HBV infection. These findings highlight the role of epigenetic modulation in h<i>NTCP</i> dysregulation, offering insights into hepatocarcinogenesis and its implications for chronic HBV infection.