O‐GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity

Abstract O‐GlcNAcylation is a posttranslational modification that regulates numerous nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes, such as transcription, signal transduction, and cell motility. Although increasing evidence has shown that elevated levels of global O‐GlcNAcylation are linked to the metastasis in hepatocellular carcinoma (HCC) cells, the underlying mechanism is still ambiguous. In this study, we demonstrated that forkhead box protein A2 (FOXA2), an essential transcription factor for liver homeostasis and HCC developing, was O‐GlcNAcylated by O‐GlcNAc transferase (OGT) and regulates HCC cells migration and invasion. Opposite FOXA2 and OGT expression tendency were observed in HCC tissues, and lower FOXA2 levels predicted a poor prognosis in HCC patients. The reduction of FOXA2 in HCC cells was found to be inversely correlated with the cellular O‐GlcNAcylation and cell migratory ability. Notably, we found that FOXA2 was modified by O‐GlcNAcylation and that O‐GlcNAcylation activated the ubiquitination degradation of FOXA2 in highly metastatic HCC cells. Although this modification did not affect FOXA2 nuclear localization capability, O‐GlcNAcylation on FOXA2 was key for attenuating FOXA2‐mediated transcription. O‐GlcNAcylation decreased the transcription of FOXA2 downstream target gene E‐cadherin and it ultimately promoted O‐GlcNAcylation‐mediated HCC cell migration and invasion. The results provide insights into the role of O‐GlcNAcylation in regulating FOXA2 activity and suggest its important implications in HCC metastasis.