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Background Deregulated methylation of tumor suppressor genes is a hallmark event in colorectal cancer (CRC) carcinogenesis.  UNC5  receptors, down-regulated in various human malignancies due to epigenetic alterations, have been proposed as putative tumor suppressor genes. In this study, we focused on the methylation-mediated inhibition of UNC5 receptors and the associated clinical significance in CRC. Methods Methylation and expression analysis was performed in TCGA datasets. And the results were confirmed in vitro in CRC cell lines treated with 5-aza-deoxycytidine. Then, the expression and epigenetic alterations of  UNC5  receptors were evaluated in clinical specimens. Moreover, the diagnostic and prognostic values of the methylation alterations were also analyzed. Results Methylation-mediated repression was observed in  UNC5C  and  UNC5D , but not in  UNC5A  and  UNC5B , which was confirmed in CRC cell lines. Except for  UNC5B , significantly elevated methylation was observed in  UNC5A ,  UNC5C , and  UNC5D  in CRC. The discrimination efficiency of the three receptors was comparable with that of  SEPT9.  Kaplan–Meier curve survival analysis showed that hypermethylation of  UNC5A ,  UNC5C  and  UNC5D  was associated with poor progression-free and overall survival. Moreover, methylation levels of  UNC5C  and  UNC5D  were independent predictors of CRC progression-free ( P  = 0.001,  P  = 0.003, respectively) and overall survival ( P  = 0.008,  P  = 0.004, respectively). Conclusions Hypermethylation of  UNC5C  and  UNC5D  mediates the repression and has promising diagnostic and prognostic values in CRC.

Promoter methylation-mediated repression of UNC5 receptors and the associated clinical significance in human colorectal cancer