Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma
Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma
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DOI：
10.1158/1535-7163.mct-16-0567-t
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发表时间：
2017-07-01
影响因子：
5.7
通讯作者：
Tan, Ching-Ting
中科院分区：
文献类型：
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作者：
Liu, Chia-Wen;Hua, Kuo-Tai;Tan, Ching-Ting
一过性化疗反应是头颈部鳞状细胞癌（HNSCC）治疗的主要障碍。组蛋白甲基转移酶G9 a在HNSCC中大量表达，是维持其恶性表型所必需的。在这项研究中，我们发现G9 a高表达与HNSCC患者化疗反应差和无病生存率显著相关。类似地，G9 a表达和酶活性在顺铂耐药的HNSCC细胞中升高。G9 a的遗传或药理学抑制使耐药细胞对顺铂敏感，增加细胞凋亡。机制研究表明，G9 a有助于谷氨酸-半胱氨酸连接酶催化亚基（GCLC）的转录激活，这导致细胞谷胱甘肽（GSH）的上调和耐药性。此外，我们观察到HNSCC患者肿瘤中G9 a和GCLC表达之间存在显著正相关。总之，我们的研究结果提供了证据表明，G9 a通过增加GSH的合成来保护HNSCC细胞免受化疗，并暗示G9 a是克服HNSCC中顺铂耐药性的有希望的靶点。
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 cisplatinresistant 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.