A Myc enhancer containing a cancer-associated SNP is required for tumorigenesis in mice.
Major finding: A Myc enhancer containing a cancer-associated SNP is required for tumorigenesis in mice.
Mechanism: Deletion of the Myc-335 enhancer reduces TCF7L2 binding and decreases Myc expression.
Impact: Myc-335 promotes tumorigenesis but does not regulate normal intestinal function in mice.
Single-nucleotide polymorphisms (SNP) in the upstream regulatory region of the MYC oncogene have been linked to elevated risk of tumorigenesis in genome-wide association studies (GWAS). In particular, the rs6983267 SNP, which is located in the Myc-335 putative enhancer element, is associated with significantly increased risk of colorectal and prostate cancer and enhanced binding of transcription factor 7-like 2 [T-cell specific, HMG-box (TCF7L2)] to the region upstream of MYC, suggesting that this SNP promotes tumor formation by altering MYC expression. To further investigate the effect of this cancer-associated SNP on MYC transcription and its contribution to tumorigenesis, Sur and colleagues analyzed the phenotype of mice in which the Myc-335 element containing this SNP was deleted. Myc-335–deficient mice were viable and fertile, in contrast with Myc−/− mice, and loss of this element did not affect intestinal epithelial proliferation or differentiation, suggesting that the Myc-335 element does not regulate normal intestinal development. However, although localization of MYC expression in intestinal crypts was similar to that in wild-type mice, Myc transcript levels were modestly decreased in Myc-335–deficient colon tissue, and TCF7L2 binding to the Myc regulatory region was diminished, validating the notion that TCF7L2 enhances Myc expression via specific binding to this element. Furthermore, deletion of Myc-335 markedly reduced the incidence of intestinal polyps in the Apcmin spontaneous tumor model, in which tumor formation is dependent on MYC activity, suggesting that Myc-335–mediated regulation of Myc expression is required for tumorigenesis. These results support a direct role for Myc-335 and the rs6983267 SNP in promoting intestinal tumor formation in mice and suggest that modulation of MYC expression may have differential effects in normal growth control and cancer pathogenesis.