Inhibiting KDM6A Phosphorylation Suppresses Glycolysis in Oral Squamous Cell Carcinoma

ABSTRACT Objectives Although KDM6A plays a pivotal role in various diseases, particularly cancer, the mechanisms underlying its influence on metabolism remain largely elusive. In this study, we aim to reveal a specific post‐translational modification of KDM6A to modulate glycolysis in oral squamous cell carcinoma (OSCC). Subjects and Methods Co‐IP and immunoblotting assays were performed to identify KDM6A‐pSer829 as a substrate of E3 ubiquitin ligase F‐Box and WD Repeat Domain Containing 7 (FBXW7). Phospho‐dead Kdm6a S829A conditional knock‐in mice were generated. The tongue tissues from these mice were collected for single‐cell RNA sequencing (scRNA‐Seq). Using 4‐nitroquinoline‐1‐oxide (4NQO) induced OSCC models in mice, the effect of KDM6A‐pS829 on cell proliferation was examined by immunofluorescent imaging. Results Co‐IP and immunoblotting established that KDM6A‐pSer829 was a critical FBXW7 recognition site, leading to its ubiquitination and degradation. scRNA‐Seq analysis of tongue tissues demonstrated significantly downregulated glycolysis in Kdm6a‐S829A mouse oral squamous cells compared to wild‐type controls. Furthermore, the Kdm6a‐S829A mutation suppressed cell proliferation in 4NQO‐induced in vivo OSCC models. Conclusions Our findings demonstrate that KDM6A‐pSer829, targeted by FBXW7 for ubiquitination and degradation, promotes glycolysis and cell proliferation in OSCC. This establishes KDM6A‐pSer829 as a critical regulator of OSCC metabolism and tumorigenesis, highlighting its potential as a novel therapeutic target.