Histone methyltransferase G9a drives chemotherapy resistance by regulating the glutamate-cysteine ligase catalytic subunit in head and neck squamous cell carcinoma
Journal
Molecular Cancer Therapeutics
Journal Volume
16
Journal Issue
7
Pages
1421-1434
Date Issued
2017
Author(s)
Liu C.-W.
Li K.-C.
Hsiao M.
Kuo M.-L.
Abstract
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. ?2017 AACR.
SDGs
Other Subjects
2 cyclohexyl n (1 isopropyl 4 piperidinyl) 6 methoxy 7 [3 (1 pyrrolidinyl)propoxy] 4 quinazolinamine; activating transcription factor 4; aldehyde dehydrogenase; beta actin; bleomycin; buthionine sulfoximine; caspase 3; cisplatin; doxycycline; fluorouracil; glutamate cysteine ligase; glutathione; glutathione ethyl ester; glyceraldehyde 3 phosphate dehydrogenase; histone H2AX; histone H3; histone methyltransferase; ligase; oxaliplatin; protein c jun; transcription factor Nrf2; cisplatin; EHMT2 protein, human; GCLC protein, human; glutamate cysteine ligase; glutathione; histocompatibility antigen; histone lysine methyltransferase; animal experiment; animal model; animal tissue; apoptosis; Article; cancer chemotherapy; cancer resistance; controlled study; disease association; disease free survival; enzyme active site; enzyme activity; enzyme inhibition; genetic analysis; head and neck squamous cell carcinoma; human; human cell; human tissue; major clinical study; nonhuman; priority journal; protein expression; transcription initiation; treatment response; upregulation; adult; aged; animal; antagonists and inhibitors; dose response; drug effects; drug resistance; drug screening; female; gene expression regulation; genetics; head and neck tumor; male; metabolism; middle aged; mouse; pathology; squamous cell carcinoma; tumor cell line; Adult; Aged; Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cisplatin; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Glutamate-Cysteine Ligase; Glutathione; Head and Neck Neoplasms; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Humans; Male; Mice; Middle Aged; Xenograft Model Antitumor Assays
Publisher
American Association for Cancer Research Inc.
Type
journal article