Integrative Analysis Reveals Comprehensive Altered Metabolic Genes Linking with Tumor Epigenetics Modification in Pan-Cancer

Figure 4

Detailed network map of transmethylation of gene expression levels in the 11 cancer types. Note: each metabolic reaction is marked with the number of tumors (out of 11 considered in our analysis) in which at least one gene in the corresponding reaction is significantly (FDR < 0.05) upregulated (red), downregulated (green), and neutral (black). If unmarked, no statistically significant change in mRNA expression was detected. There were three metabolites as methyl donors: methionine, folate, and betaine. All of them provided the methyl group to SAM through their metabolic cycle. Betaine was produced from choline by CHDH. The transporters of choline and folate were SLC44A4 and SLC19A1. Methionine and ATP were catalyzed into SAM by MATs. SAM donated its methyl group to DNA or histone in reactions catalyzed by MTs: DNMT1, DNMT3A, and DNMT3B. SAH was the byproduct of methylation reactions process from SAM. Then, SAH was regulated by the enzyme AHCY, which reversibly made this metabolite into adenosine and homocysteine. Homocysteine was used to produce methionine with the demethylation of folate and betaine through two enzymes: MS and BHMT. SLC19A1: solute carrier family 19 member 1; SLC44A4: solute carrier family 44 member 4; DHFR: dihydrofolate reductase; CHDH: choline dehydrogenase; BHMT: betaine-homocysteine S-methyltransferase; AHCY: adenosylhomocysteinase; MTHFD1: methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1; MTHFD2: methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2, methenyltetrahydrofolate cyclohydrolase; MAT1A: methionine adenosyltransferase 1A; MAT2A: methionine adenosyltransferase 2A; DNMT1: DNA methyltransferase 1; DNMT3A: DNA methyltransferase 3 alpha; DNMT3B: DNA methyltransferase 3 beta; THF: tetrahydrofuran; MTHF: methyltetrahydrofolate; SAM: S-adenosyl-L-methionine; SAH: S-adenosyl-L-homocysteine.