FOXA2 inhibits doxorubicin-induced apoptosis via transcriptionally activating HBP rate-limiting enzyme GFPT1 in HCC cells.

Apoptosis plays an important role in both carcinogenesis and cancer treatment. Understanding the mechanisms through which resistance to apoptosis occurs in cancer cells has huge implications for cancer treatment. Although pieces of evidence have shown that elevated levels of global O-GlcNAcylation play an anti-apoptotic role in myriad cancers, the underlying mechanism is still ambiguous. In this study, we demonstrated that FOXA2, an essential transcription factor for liver homeostasis and hepatocellular carcinoma (HCC) development, inhibits doxorubicin (DOX)-induced apoptosis through elevating cellular O-GlcNAcylation in HCC cells. In response to DOX treatment, elevated FOXA2 and global O-GlcNAcylation level was observed in HCC cells, and higher FOXA2 levels indicated lower levels of DOX-induced apoptosis. Subsequently, we demonstrated that FOXA2 is a direct transcriptional activator of the hexosamine biosynthetic pathway (HBP) rate-limiting enzyme GFPT1. The upregulation of FOXA2 expression induced the synthesis of intracellular UDP-GlcNAc, which is the sugar substrate of O-GlcNAcylation produced by the HBP. The flux through the HBP elevated the global O-GlcNAcylation level and led to the activation of survival signaling pathways in HCC cells. Furthermore, GFPT1 was proved to be an important downstream regulator of FOXA2-mediated apoptotic suppression. These results provide insights into the molecular mechanism by which FOXA2 inhibits DOX-induced HCC cell apoptosis and suggest that targeting FOXA2 might offer a new strategy for HCC treatment.