NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration
- PMID: 40371884
- DOI: 10.1002/path.6430
NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the most common malignant tumors in the head and neck region, characterized by a high recurrence rate and early metastasis. Despite advances in treatment, patient outcomes and prognosis remain poor, highlighting the urgent need for new therapeutic strategies. Recent research has increasingly focused on targeting glucose metabolism as a therapeutic strategy for cancer, revealing multiple promising targets and potential drugs. However, the metabolic heterogeneity among tumors leads to variable sensitivity to metabolic inhibitors in different patients, limiting their clinical utility. In this study, we employed bioinformatics analysis, cell experiments, animal models, and multi-omics approaches to reveal differences in glucose metabolism phenotypes among HNSCC patients and elucidated the underlying molecular mechanisms driving these differences. Our findings showed that NSD1 mutation status affects the glucose metabolism phenotype in HNSCC, with NSD1 wild-type HNSCC exhibiting higher mitochondrial respiration and NSD1 mutant HNSCC showing weaker mitochondrial respiration but enhanced glycolysis. We further demonstrated that NSD1 regulates mitochondrial respiration in HNSCC via epigenetic modulation of the TGFB2/PPARGC1A signaling axis. Additionally, we found that NSD1 wild-type HNSCC is more sensitive to mitochondrial respiration inhibitors, whereas NSD1 mutant HNSCC shows increased sensitivity to glycolysis inhibitors. In summary, we found that NSD1 can epigenetically regulate the TGFB2/PPARGC1A axis to modulate mitochondrial respiration and sensitivity to metabolic inhibitors in HNSCC. These findings suggest a novel strategy for selecting metabolic inhibitors for HNSCC based on the NSD1 gene status of patients. © 2025 The Pathological Society of Great Britain and Ireland.
Keywords: HNSCC; NSD1; epigenomics; glucose metabolism; glycolysis; histone modification; metabolic inhibitor; metabolism heterogeneity; mitochondrial respiration; mutation.
© 2025 The Pathological Society of Great Britain and Ireland.
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References
-
- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024; 74: 229–263.
-
- Bugshan A, Farooq I. Oral squamous cell carcinoma: metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis. F1000Res 2020; 9: 229.
-
- Sisodiya SM. Precision medicine and therapies of the future. Epilepsia 2021; 62: S90–S105.
-
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
-
- Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23: 27–47.
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- CIFMS2019-12M-5-004/CAMS Innovation Fund for Medical Sciences
- 2024YFFK0393/Fund of Sichuan Provincial Department of science and technology
- LCYJ2023-DL-2/Research and Develop Program, West China Hospital of Stomatology, Sichuan University
- 81902784/National Natural Science Foundation of China
- 82370974/National Natural Science Foundation of China
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