KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC

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.

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Publication Details

Journal
Cell Death and Disease
Published
2025-11-03
DOI
https://doi.org/10.1038/s41419-025-08130-w
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
0.00

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article

KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC

Ming Yan, Yikang Ji, Jun Chen, Xinhua Pan et al.
Cell Death and Disease
Epigenetics and DNA Methylation
article

KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC

Ming Yan, Yikang Ji, Jun Chen, Xinhua Pan, W H Chen, Xin Hu, X. Jessie Yang, Jianjun Zhang, Mei Zhang, Xu Wang, Yu Zhang, Zhen Zhang, Qin Xu, Xin Chen, Xing Xu, Mi Zhang
article en

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.

Cell Death and DiseaseVol. 16(1)
Shanghai Jiao Tong University (CN), National Clinical Research Center for Digestive Diseases (CN), Shanghai Stomatological Hospital (CN), Shanghai Ninth People's Hospital (CN), National Clinical Research (US)
National Natural Science Foundation of China, Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University
Openalex Percentile: Top 71%
Epigenetics and DNA Methylation
DOIOpen Access PDFOpenAlex
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