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Supplementary Figures from 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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posted on 2023-04-03, 14:41 authored by Chia-Wen Liu, Kuo-Tai Hua, Kai-Chun Li, Hsiang-Fong Kao, Ruey-Long Hong, Jenq-Yuh Ko, Michael Hsiao, Min-Liang Kuo, Ching-Ting Tan

Supplementary figure 1. Characterization of the cisplatin-resistant HNSCC cell lines. Supplementary figure 2. Genetic or pharmacological inhibition of G9a promotes cisplatin-induced apoptosis in SAS-CR cells.Supplementary figure 3. Depletion of G9a increases the sensitivity to cisplatin in OECM-1 cells.Supplementary figure 4. Depletion of G9a increases the platinum-DNA adduct accumulation. Supplementary figure 5. Inhibition of G9a by shRNA or enzymatic inhibitor decreases intracellular GSH levels. Supplementary figure 6. Multi-drug resistance to chemotherapeutic agents in G9a-overexpressed SAS cells. Supplementary figure 7. Effect of G9a on the expression of GSH synthesis enzymes. Supplementary figure 8. The expression of GSH synthesis enzymes in mouse xenograft tumors. Supplementary figure 9. ATF4 upregulates GCLC in cisplatin-resistant cells. Supplementary figure 10. Upregulated GCLC is required for G9a to promote cisplatin resistance.

Funding

Ministry of Science and Technology, Taiwan

History

ARTICLE 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. Mol Cancer Ther; 16(7); 1421–34. ©2017 AACR.