Inhibiting KDM6A Phosphorylation Suppresses Glycolysis in Oral Squamous Cell Carcinoma

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).

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.

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.

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.