Document Type : Original Article
Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
Precision Diagnosis and Treatment Center of Jinhua City, Jinhua, Zhejiang Province, China
Department of General Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
Department of Respiratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
Objective: Tumor drug resistance is a vital obstacle to chemotherapy in lung cancer. Methionine adenosyltransferase
2A has been considered as a potential target for lung cancer treatment because targeting it can disrupt the tumorigenicity of lung tumor-initiating cells. In this study, we primarily observed the role of methionine metabolism in cisplatin-resistant lung cancer cells and the functional mechanism of MAT2A related to cisplatin resistance.
Materials and Methods: In this experimental study, we assessed the half maximal inhibitory concentration (IC50)
of cisplatin in different cell lines and cell viability via Cell Counting Kit-8. Western blotting and quantitative real-time
polymerase chain reaction (qRT-PCR) was used to determine the expression of relative proteins and genes. Crystal violet staining was used to investigate cell proliferation. Additionally, we explored the transcriptional changes in lung
cancer cells via RNA-seq.
Results: We found H460/DDP and PC-9 cells were more resistant to cisplatin than H460, and MAT2A was overexpressed
in cisplatin-resistant cells. Interestingly, methionine deficiency enhanced the inhibitory effect of cisplatin on cell activity and the pro-apoptotic effect. Targeting MAT2A not only restrained cell viability and proliferation, but also contributed to
sensitivity of H460/DDP to cisplatin. Furthermore, 4283 up-regulated and 5841 down-regulated genes were detected in
H460/DDP compared with H460, and 71 signal pathways were significantly enriched. After treating H460/DDP cells with
PF9366, 326 genes were up-regulated, 1093 genes were down-regulated, and 13 signaling pathways were significantly
enriched. In TNF signaling pathway, CAS7 and CAS8 were decreased in H460/DDP cells, which increased by PF9366
treatment. Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under
methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366.
Conclusion: Methionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis,
DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer
cells to cisplatin.