HBx protein contributes to liver carcinogenesis by H3K4me3 modification

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Abstract

Cancer is typically considered as a genetic and epigenetic disease. While numerous studies have indicated that aberrant structure, function or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)‐induced hepatocellular carcinoma (HCC) remains unknown. In this study, we found that the WD repeat domain 5 protein (WDR5)—a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification—is highly expressed in HBV‐related HCC and promotes HCC development. WDR5 plays a critical role in HBV‐driven cell proliferation and tumor growth in mice, and the WDR5‐0103 small molecule inhibitor of WDR5 activity compromises HBV‐ and HBx‐driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve the HBV x protein (HBx) through its stabilization of the WDR5 protein by inhibiting the interaction between the damage‐specific DNA binding protein 1/ cullin‐4 (DDB1‐CUL4) and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome‐wide and promotes genome‐wide H3K4me3 modification via WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5, through its α‐helix domain. WDR5 was also found to promote HBV transcription via H3K4 modification of cccDNA minichromosome, and WDR5‐0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor promoting function in a WDR5‐dependent manner.

Conclusion

Our data reveals that WDR5 is a key epigenetic determinant of HBV‐induced tumorigenesis and that the HBx‐WDR5‐H3K4me3 axis may be a potential therapeutic target in HBV‐induced liver pathogenesis.

https://doi.org/10.1002/hep.30947