Background and Purpose: O-GlcNAcylation is a significant protein posttranslational modification
with O-linked β-N-acetylglucosamine (GlcNAc) for intracellular signaling. Elevated O-GlcNAcylation contributes
to cell proliferation, cell migration, cell apoptosis and signal transduction in various cancers. However, the
expression level and functional role of O-GlcNAcylation in Hypopharyngeal Squamous Cell Carcinoma
(HSCC) is not clearly elucidated. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a master transcriptional
factor that has been found to be aberrantly activated in HSCC. Here, we provide a molecular rationale between
O-GlcNAcylation and Nrf2 in HSCC patients.
Methods: The protein levels of O-GlcNAcylation and Nrf2 in HSCC tissues were detected by immunohistochemistry
technique and western blot analysis. Then, O‐GlcNAcylation knockdown HSCC cells were applied
in this study. Cell proliferation was detected by CCK8, colony-forming analysis, and cell cycle assays. Cell
migration and invasion ability was evaluated by transwell assays. Cell apoptosis was measured by TUNEL
Results: O-GlcNAcylation was obviously up-regulated in HSCC tissues, which correlated with tumor size and
lymph node metastasis. In addition, the protein level of Nrf2 was found to positively correlate with the expression
of O‐GlcNAcylation both in vivo and in vitro. Knockdown of O-GlcNAcylation significantly inhibited HSCC
cell growth, suppressed cell migration, and promoted cell apoptosis, whereas overexpression of Nrf2 reversed
these phenotypes. Mechanismly, the upregulation of O-GlcNAcylation promoted the phosphorylation of Akt,
leading to the stabilization of Nrf2; this could be attenuated by inhibition of the PI3K/Akt signaling pathway.
Conclusion: Here, we provide a molecular association between O-GlcNAcylation and Nrf2 in HSCC patients,
thus providing valuable therapeutic targets for the disease.