UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma

Abstract

Ubiquitination factor E4B (UBE4B) is crucial to the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Evidence suggests that aberrant epigenetic modifications significantly contribute to HCC carcinogenesis, making epigenetic mechanisms a promising area for therapeutic intervention. However, the precise role of UBE4B in the epigenetic dysregulation observed in HCC remains elusive. In this study, we silenced UBE4B in HCC cells and exposed them to a panel of epigenetic compounds. Notably, only bromodomain and extraterminal inhibitors (BETis) exhibited resistance to UBE4B silencing, while restoring UBE4B expression partially reversed this resistance. Furthermore, UBE4B deletion led to decreased growth rates and impaired proliferation, resulting in cell cycle arrest and diminished tumorigenicity. However, this deletion did not affect the cell cycle arrest induced by BETi. Interestingly, KLHL22, a ubiquitin substrate of UBE4B, accumulated in UBE4B-deleted cells. Knockdown of KLHL22 restored sensitivity to BETi, accompanied by downregulation of JAK2 and upregulation of its negative regulator, LNK. Additionally, UBE4B deletion resulted in decreased LNK expression, and LNK knockdown increased JAK2 expression and mediated resistance to BETi. Increased JAK2 subsequently targeted PIM1, further reducing the inhibitory effect of BETi. Directly silencing PIM1 in UBE4B-deleted cells restored BETi sensitivity. Overall, our findings provide novel insights into the relationship between UBE4B expression and BETi sensitivity, which is mediated through the KLHL22-JAK2-PIM1 regulatory axis. These findings not only deepen our understanding of the mechanisms underlying HCC progression but also suggest that targeting this axis may present a promising therapeutic strategy for enhancing the treatment outcomes of HCC.