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Emerging evidence suggests that hypermethylation of  HOXD10  plays an important role in human cancers. However, the biological and clinical impacts of  HOXD10  overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of  HOXD10  in paired cancer and normal tissues ( n  = 42) by using pyrosequencing, followed by validation of the methylation status of  HOXD10  from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of  HOXD10  was characterized in cell lines. We further evaluated the effects of  HOXD10  and its targets on chemoresistance in our established resistant cell lines and clinical cohort ( n  = 66).  HOXD10  was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally,  HOXD10  acts as a tumor suppressor gene, in which  HOXD10 -expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the  HOXD10  promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce  HOXD10  expression.  HOXD10  regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of  HOXD10  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  HOXD10  is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of  HOXD10  activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer