# KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC

## TL;DR

This study shows how KDM6A phosphorylation affects cancer metabolism in head and neck cancer, offering a new therapeutic target.

## Contribution

The discovery that KDM6A phosphorylation at Ser829 drives glycolytic reprogramming through PER2 silencing in HNSCC is novel.

## Key findings

- Phosphorylation of KDM6A at Ser829 is prevalent in HNSCC and other solid tumors.
- Phosphorylated KDM6A promotes glycolytic reprogramming by silencing PER2 via H3K27Me3.
- This epigenetic-metabolic axis supports tumor growth in vitro and in vivo.

## Abstract

As a key tumor suppressor, KDM6A plays critical roles in maintaining epigenetic homeostasis and suppressing tumorigenesis. However, the regulatory mechanisms controlling KDM6A activity in head and neck squamous cell carcinoma (HNSCC) are not well defined. In this study, we employed tissue microarray analysis of clinical specimens to identify Ser829 as a predominant phosphorylation site of KDM6A in HNSCC and other solid tumors. Using mass spectrometry and biochemical assays, we demonstrate that CDK1-mediated phosphorylation at Ser829 enhances KDM6A binding to SFN, leading to its nuclear export and functional inactivation. Integrated chromatin profiling and metabolic analyses revealed that phosphorylated KDM6A-pSer829 drives glycolytic reprogramming through H3K27Me3-dependent transcriptional silencing of PER2, ultimately promoting tumor growth in vitro and in vivo. These findings establish KDM6A post-translational modification as a pivotal regulator of metabolic adaptation in HNSCC progression, providing a potential therapeutic target for combating cancer through this epigenetic-metabolic axis.