The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1

Abstract

Folate (vitamin B9) is a common name for a group of coenzymes that function as carriers of chemical moieties called one-carbon groups in numerous biochemical reactions. The combination of these folate-dependent reactions constitutes one-carbon metabolism, the name synonymous to folate metabolism. Folate coenzymes and associated metabolic pathways are vital for cellular homeostasis due to their key roles in nucleic acid biosynthesis, DNA repair, methylation processes, amino acid biogenesis, and energy balance. Folate is an essential nutrient because humans are unable to synthesize this coenzyme and must obtain it from the diet. Insufficient folate intake can ultimately increase risk of certain diseases, most notably neural tube defects. More than 20 enzymes are known to participate in folate metabolism. Single-nucleotide polymorphisms (SNPs) in genes encoding for folate enzymes are associated with altered metabolism, changes in DNA methylation and modified risk for the development of human pathologies including cardiovascular diseases, birth defects, and cancer. ALDH1L1, one of the folate-metabolizing enzymes, serves a regulatory function in folate metabolism restricting the flux of one-carbon groups through biosynthetic processes. Numerous studies have established that ALDH1L1 is often silenced or strongly down-regulated in cancers. The loss of ALDH1L1 protein positively correlates with the occurrence of malignant tumors and tumor aggressiveness, hence the enzyme is viewed as a candidate tumor suppressor. ALDH1L1 has much higher frequency of non-synonymous exonic SNPs than most other genes for folate enzymes. Common SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717, and rs4646750 in ALDH1L1 exons characterize more than 97% of Europeans while additional common variants are found in other ethnic populations. The effects of these SNPs on the enzyme is not clear but studies indicate that some coding and non-coding ALDH1L1 SNPs are associated with altered risk of certain cancer types and it is also likely that specific haplotypes define the metabolic response to dietary folate. This review discusses the role of ALDH1L1 in folate metabolism and etiology of diseases with the focus on non-synonymous coding ALDH1L1 SNPs and their effects on the enzyme structure/function, metabolic role and association with cancer.

Association Between SNPs in the One-Carbon Metabolism Pathway and the Risk of Female Breast Cancer in a Chinese Population

“…18 ALDH1L1 gene expression is down-regulated in cancer, and low ALDH1L1 expression is associated with the occurrence and malignant expression of tumors. [44][45][46] In this study, we observed that ALDH1L1 rs2002287 was not associated with the overall risk of BC, while, in the subgroup analysis, we observed that PR-positive women who carried the C allele have a higher risk of BC, which is consistent with a previous report. 47 However, a conflicting conclusion was reported that rs2002287 was associated with a decreased risk of BC, 44 which may be attributed to the fact that the effect of SNP on cancer has racial specificity.…”

“…[44][45][46] In this study, we observed that ALDH1L1 rs2002287 was not associated with the overall risk of BC, while, in the subgroup analysis, we observed that PR-positive women who carried the C allele have a higher risk of BC, which is consistent with a previous report. 47 However, a conflicting conclusion was reported that rs2002287 was associated with a decreased risk of BC, 44 which may be attributed to the fact that the effect of SNP on cancer has racial specificity. 48 At the same time, this is the first study on the relationship between rs2002287 and BC risk in Chinese people, so large sample sized case-control studies are needed.…”

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

“…78 Although ALDH1L1 is overexpressed in NSCLC and GC cancer, 79,80 ALDH1L1 is reported profoundly downregulated or silenced in cancers, rendering it a candidate tumor suppressor. 81,82 Nevertheless, ALDH1L2 is highly expressed and presents as an independent prognostic factor for overall survival in melanoma, PDAC, and CRC. 77,78,83 Depletion of ALDH1L2 markedly decreases the NADPH/NADP + and GSH/GSSG ratios, reduces the circulating tumor cells in blood and alleviates the metastatic burden.…”

Associations between ALDH Genetic Variants, Alcohol Consumption, and the Risk of Nasopharyngeal Carcinoma in an East Asian Population

“…In studies involving East Asian populations, the presence of genetic polymorphisms in ADH1B (rs1229984) and ALDH2 (rs671), as well as alcohol consumption, individually or in combination [13], increase the risk of breast cancer [36], HNC [17], and esophageal cancer [18,35]. Moreover, research has shown that alcohol consumption affects two major folate-metabolizing enzymes, ALDH1L1 and ALDH1L2, with a possible synergistic effect on carcinogenesis [37,38]. In this study, SNPs rs671 located on ALDH2 and rs10778364 located on ALDH1L2 were significantly associated with an increased risk for NPC, with or without alcohol consumption.…”