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Published on: March 17, 2023
NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by
Shouyi Tang1,2, Qing Wang1, Zhen Wang1
1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China.
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.
Insights
Head and neck squamous cell carcinomas (HNSCCs) exhibit distinct glucose metabolism based on NSD1 gene status. This finding guides personalized selection of metabolic inhibitors for improved HNSCC treatment strategies.
Area of Science:
- Oncology
- Cancer Metabolism
- Epigenetics
Background:
- Head and neck squamous cell carcinomas (HNSCCs) have poor prognoses and high recurrence rates.
- Targeting cancer glucose metabolism is a promising therapeutic avenue, but tumor heterogeneity limits drug efficacy.
- Understanding metabolic differences in HNSCC is crucial for developing effective treatments.
Purpose of the Study:
- To investigate glucose metabolism phenotypes in HNSCC patients.
- To elucidate the molecular mechanisms driving metabolic heterogeneity.
- To identify patient-specific therapeutic strategies targeting HNSCC metabolism.
Main Methods:
- Bioinformatics analysis
- Cell experiments
- Animal models
- Multi-omics approaches
- Analysis of NSD1 mutation status
Main Results:
- NSD1 mutation status significantly impacts HNSCC glucose metabolism.
- NSD1 wild-type HNSCC shows higher mitochondrial respiration; NSD1 mutant HNSCC exhibits enhanced glycolysis.
- NSD1 epigenetically regulates the TGFB2/PPARGC1A axis, influencing mitochondrial respiration.
- Differential sensitivity to metabolic inhibitors observed based on NSD1 status.
Conclusions:
- NSD1 status dictates HNSCC metabolic phenotype and drug sensitivity.
- NSD1 epigenetically controls mitochondrial respiration via the TGFB2/PPARGC1A pathway.
- Tailoring metabolic inhibitor selection based on NSD1 mutation status offers a novel therapeutic strategy for HNSCC.
