br Increased expression of GART TYMS SHMT and MTR
Increased 22144-77-0 of GART, TYMS, SHMT2, and MTR were associated with sensitivity to multiple agents (Table 1; Figs. 1 and 3). Expression levels of GART and TYMS, both of which encode products involved in nucleotide synthesis, were negatively associated with log(IC50) of 24 and 21 drugs, respectively (r between −0.301 and −0.362 for GART and −0.301 and −0.372 for TYMS). Overexpression of TYMS and GART had been associated with a late relapse of child-hood acute lymphoblastic leukemia . Additionally, elevated TYMS gene and protein expression had been correlated with poorer overall survival of colorectal patients, and some stud-ies also reported an association of a tandem repeat poly-morphism in the TYMS gene promoter with survival of pa-tients with colorectal cancer [69,90]. Similarly, GART protein 29
Table 2 Pearson correlation results among expression levels of one-carbon metabolism genes which satisfied r > 0.3 and FDR adjusted p < 0.05.
OCM Gene 1 OCM Gene 2 r FDR adjusted p
r: Pearson correlation coefficient.
Correlation results listed in the table are based on 1036 CCLE cell lines with available expression microarray information.
overexpression had been associated with poorer overall sur-vival of glioma patients and with progression and overall sur-vival of hepatocellular carcinoma [91,92].
Expression of SHMT2, which encodes mitochondrial ser-ine hydroxymethyl transferase 2 and is involved in glycine biosynthesis , was correlated with response to 17 agents (r between −0.305 and −0.403). An earlier study had shown an association of increased SHMT2 gene expression with shorter overall survival rates of patients with colorectal cancer and lung adenocarcinoma . Expression of the methionine synthase gene MTR, which affects cellular methylation pro-cesses by participating in remethylation of homocysteine, was associated with 8 agents (r between −0.300 and −0.330). An earlier meta-analysis of case-control patient data had sug-gested an association of the A2756G polymorphism in that gene with susceptibility to acute lymphoblastic leukemia and colorectal cancer .
Expression levels of multiple one-carbon metabolism genes were correlated
Table 2 shows the most prominent statistically significant cor-relations among expression levels of OCM genes which satis-fied Pearson r > 0.3 and FDR adjusted p < 0.05. Expression
Fig. 3 Antitumor agents associated with GART, MTR, SHMT2, and TYMS gene expression from Table 1, satisfying Pearson r > 0.3 and FDR adjusted p < 0.05.
levels were positively correlated among many OCM genes, in-cluding 26 out of the 27 correlations listed in Table 2, which is consistent with previously reported associations in ALL patients . This suggests a possibility that expression of some of these genes in cancer cells may be co-regulated. The strongest correlation was observed between expres-sion levels of TYMS and DHFR (r = 0.575, FDR adjusted
p = 4.48 × 10−89). Previously, we observed that both genes had similar patterns of expression response to several anti-cancer drugs in the NCI-60 cell lines . Products of these genes catalyze related reactions in the OCM pathway. TYMS catalyzes the conversion of 5,10-methylenetetrahydrofolate (5,10-methylene-THF) to dihydrofolate (DHF) during the con-version of deoxyuridine monophosphate into deoxythymidine monophosphate in the process of thymidylate biosynthesis, whereas the DHFR catalyzes the reduction of DHF to tetrahy-drofolate (THF), and also the conversion of dietary folate to DHF and then to THF [8,85,95]. The TYMS and DHFR genes are located in separate genome regions on different chromo-somes (18p11.32 and 5q14.1, respectively), suggesting that their co-regulation is likely related to their functional activity rather than to their chromosomal co-localization.
Expression of one-carbon metabolism genes was strongly correlated with transcriptional levels of multiple components of drug target pathways
Expression of many genes encoding direct drug targets or target pathway components of the drug agents listed in Table 1 was strongly correlated with expression levels of mul-tiple OCM genes. The complete list of Pearson correlation results between OCM genes and components of target path-ways for each agent is provided in Supplementary Table 4. The strongest significant correlations (Pearson r > 0.45, FDR adjusted p < 0.05) are shown in Table 3. NNMT had the strongest associations with molecular drug targets, with 21 associations that had r between 0.453 and 0.693 (Table 3), and the total of 90 associations satisfying a weaker threshold of r > 0.3. DHFR and TYMS also had mul-tiple significant correlations with r > 0.45. Other genes that were strongly associated with expression of molecular targets included MTHFD1, MTHFD2L, GART, and SHMT1 ( r > 0.45; Table 3). In addition, expression of these and other OCM-related genes including AHCY, ATIC, BHMT, FTCD, MAT2A, MAT2B, MTHFR, MTHFS, MTR, MTRR, PEMT, SHMT2, ALDH2, and folate receptors and transporters FOLR1, FOLR2, SLC19A1, and SLC46A1 was correlated with expression of multiple target pathway components us-ing a weaker threshold of r > 0.3 (Supplementary Table 4). Interestingly, 408 out of 516 significant correlations between OCM and target gene expression in Supplementary Table 4 satisfying r > 0.3 were positive, including 43 out of 45 strongest associations with r > 0.45 (Table 3). Strong posi-tive correlations of OCM gene expression with molecular drug targets may provide a possible explanation for associations of OCM genes with drug sensitivity (Table 1; Supplementary Table 1).