The promoter methylation drives down-regulation mode of HIC1 in gastric cancer, its molecular characteristics and downstream functional pathways.

Gastric cancer is a common malignant tumor of the gastrointestinal tract with a high incidence and mortality rate. Previous results have suggested that the HIC1 gene might be a tumor suppressor candidate in gastric cancer. However, several critical points need to be elucidated: (1) The correlation of HIC1 promoter methylation with its specific expression level in gastric cancer; (2) The molecular characterization of HIC1 promoter methylation; (3) The possible mechanism by which HIC1 performs its inhibitory role in gastric cancer. To address these questions, we retrieved data from TCGA database to analyze HIC1 promoter methylation levels and transcript expression data, and performed targeted region bisulfite sequencing on three stable HIC1 down-regulated cell lines and normal control cell lines, and performed whole transcriptome and metabolite assays in HIC1 knockout cell lines by CRISPR-Cas9 technique. Results demonstrated that HIC1 promoter hypermethylation might be a crucial driving force leading to its down-regulation in HIC1 expression in gastric cancer. This implicated that promoter CG methylation of HIC1 might play a major role in the development of gastric carcinogenesis. Besides, HIC1 may suppress gastric cancer progression by maintaining the normal cellular metabolism, and inhibiting the mTOR signaling pathway activity.