Epigenetic silencing of the candidate tumor suppressor gene GLDC in gastric carcinoma

Abstract

The metabolic enzyme, glycine dehydrogenase (GLDC) involved in glycine metabolism is known for non-ketotic hyperglycinemia but not for cancers. Recently, it has been only reported that GLDC drives tumor initiating cells (TICs) and tumorigenesis in non-small cell lung cancer. In our study, we performed the oligonucleotide microarray analysis and the Infinium Human Methylation27 BeadChip analysis to identify potential tumor suppressor genes showing down-regulated expression and promoter hypermethylation in ten gastric cancer (GC) cell lines. Among several candidate genes, the GLDC was silenced in eight out of ten GC cell lines and the down-regulation of GLDC was closely linked to the promoter methylation. Knockdown of GLDC increased the cell proliferation, migration, invasion, colony formation and reduced apoptosis. Promoter methylation of GLDC was detected in 79.4% and loss of protein expression was detected in 82.7% in GC tissues. Loss of GLDC protein expression by immunohistochemistry was found to be significantly associated with WHO classification (p <0.001), Laurens classification (p <0.001) in 410 gastric cancer patients. With GC tissues and paired normal gastric tissues, we found that mRNA and protein expression was down-regulated (72.0% and 68.5%) in GC tissues compared to normal gastric tissues. In GC tissues, hypermethylation of GLDC had significant correlation with downregulation of GLDC protein as compared with normal gastric tissues. In summary, GLDC is a candidate for tumor suppressor gene in gastric carcinogenesis and the hypermethylation of GLDC gene is the main reason for the silencing of the GLDC.