Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma
Autor: | Kuo Tai Hua, Ruey-Long Hong, Ching-Ting Tan, Jenq-Yuh Ko, Michael Hsiao, Kai-Chun Li, Min-Liang Kuo, Chia-Wen Liu, Hsiang-Fong Kao |
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Rok vydání: | 2017 |
Předmět: |
Adult
Male 0301 basic medicine Cancer Research Glutamate-Cysteine Ligase Cell Biology Disease-Free Survival Mice 03 medical and health sciences chemistry.chemical_compound Downregulation and upregulation Cell Line Tumor Histocompatibility Antigens medicine Animals Humans Aged Regulation of gene expression Cisplatin Dose-Response Relationship Drug Squamous Cell Carcinoma of Head and Neck Histone-Lysine N-Methyltransferase Glutathione Middle Aged medicine.disease Xenograft Model Antitumor Assays Head and neck squamous-cell carcinoma Molecular biology Gene Expression Regulation Neoplastic stomatognathic diseases 030104 developmental biology medicine.anatomical_structure GCLC Oncology chemistry Drug Resistance Neoplasm Head and Neck Neoplasms Histone methyltransferase Carcinoma Squamous Cell Female medicine.drug |
Zdroj: | Molecular Cancer Therapeutics. 16:1421-1434 |
ISSN: | 1538-8514 1535-7163 |
Popis: | Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421–34. ©2017 AACR. |
Databáze: | OpenAIRE |
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