Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming in non-small cell lung cancer cells
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These data are the original data from the manuscript entitled "Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming in non-small cell lung cancer cells". Below is a summary of the manuscript. Methionine adenosyltransferase 2A (MAT2A) links metabolic reprogramming with epigenetic regulation by generating S-adenosylmethionine (SAM) in the methionine cycle. The pattern of MAT2A regulation in metabolic reprogramming within non-small cell lung cancer (NSCLC) remains poorly understood. Current MAT2A inhibitors exhibit limited efficacy and additional therapeutic strategies need to be explored. Here, we employed proteomics and metabolomics in NSCLC cell lines treated with siRNA targeting MAT2A or the inhibitor AG-270, complemented by targeted metabolomics, RT-qPCR and ATAC-seq, to systematically characterize MAT2A-rewired metabolic reprogramming and identify potential combination strategies. Both MAT2A knockdown and inhibition significantly disrupt fatty acid biosynthesis, cholesterol metabolism, glycolysis and the transsulfuration pathway. In fatty acid biosynthesis, MAT2A influences the expression of key genes FASN and SCD and the levels of key metabolites palmitic acid (PA) and oleic acid (OA), as exogenous PA reverses the cell growth inhibition caused by AG-270. Furthermore, this metabolic link supports the rationale for combining AG-270 with the FASN inhibitor TVB-2640. In cholesterol metabolism, MAT2A regulates biosynthesis and efflux, and combining AG-270 with a liver X receptor agonist, which facilitates cholesterol efflux, augments anti-tumor efficacy. In energy metabolism, MAT2A influences glycolysis via regulation of HIF1A. The GLUT1 inhibitor which prevents glucose uptake, exhibits a synergetic effect when combined with AG-270. In the transsulfuration pathway, MAT2A transcriptionally regulates CBS, a key enzyme for cysteine biosynthesis. Combination treatments of AG-270 with inhibitors targeting genes upregulated in response to AG-270, such as PHGDH, which produces serine for cysteine biosynthesis, and SLC7A11, which mediates cysteine uptake, exhibit synergetic effects. Overall, our findings identify MAT2A as a critical regulator of metabolism in NSCLC and propose rational combination strategies to enhance MAT2A inhibitor efficacy.
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Institutions
- University of Chinese Academy of SciencesBeijing, Beijing