Restoring Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer.

Emerging evidence suggests that hypermethylation of plays an important role in human cancers. However, the biological and clinical impacts of overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of in paired cancer and normal tissues ( = 42) by using pyrosequencing, followed by validation of the methylation status of from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of was characterized in cell lines. We further evaluated the effects of and its targets on chemoresistance in our established resistant cell lines and clinical cohort ( = 66). was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, acts as a tumor suppressor gene, in which -expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the promoter, and demethylation by 5-Aza-2'-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce expression. regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).