Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

• Published in: Molecular cancer therapeutics Vol. 16; no. 7; pp. 1421 - 1434
• Main Authors: Liu, Chia-Wen, Hua, Kuo-Tai, Li, Kai-Chun, Kao, Hsiang-Fong, Hong, Ruey-Long, Ko, Jenq-Yuh, Hsiao, Michael, Kuo, Min-Liang, Tan, Ching-Ting
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01-07-2017
• Subjects: Adult; Aged; Animals; Apoptosis; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Catalysis; Cell Line, Tumor; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cysteine; Disease-Free Survival; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - genetics; Enzymatic activity; Female; Gene Expression Regulation, Neoplastic - drug effects; Glutamate-cysteine ligase; Glutamate-Cysteine Ligase - genetics; Glutathione; Glutathione - genetics; Glutathione - metabolism; Head & neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Histocompatibility Antigens - genetics; Histone methyltransferase; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - genetics; Humans; Male; Mice; Middle Aged; Patients; Pharmacology; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Transcription activation; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0567-T

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.
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