While upstream loss-of-function mutations of the von Hippel-Lindau tumor suppressor gene (VHL) or aberrant signaling may result in CXCR4 overexpression in some cancers [39,40], other studies point to epigenetic regulation of CXCR4. For example, cytosine methylation (5mC) occurs widely in cancers including CRC [41,42,43,44,45,46]. This evidence concerns the gene VHL and cancer.