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
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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