Abstract
The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.
Highlights
Received: 18 November 2016Accepted: 18 April 2017Published: 06 June 2017Deregulated expression of the MYC oncogene is associated with many cancer types (Reviewed in Albihn et al, 2010; Dang, 2012; Evan, 2012)
To dissect functional significance of the 8q24 region during normal development, we generated series of Myc alleles in mice using homologous recombination in ES cells. These include the Myc-335 enhancer deletion allele we have described previously (Sur et al, 2012b), and deletions of two additional conserved enhancer elements, Myc-196 and Myc-540, both of which are active in mouse intestine and colorectal cancer cells
The risk alleles for different cancer types are located in multiple distinct linkage disequilibrium blocks, indicating that different variants contribute to different cancer types
Summary
Received: 18 November 2016Accepted: 18 April 2017Published: 06 June 2017Deregulated expression of the MYC oncogene is associated with many cancer types (Reviewed in Albihn et al, 2010; Dang, 2012; Evan, 2012). MYC acts primarily as a transcriptional activator that increases expression of many genes required for RNA and protein synthesis above the level that is required in resting cells. Aberrantly elevated levels of MYC drive global amplification of transcription rates, providing the cells with necessary resources for rapid proliferation (see, for example Brown et al, 2008; van Riggelen et al, 2010; Ji et al, 2011; Lin et al, 2012; Sabò et al, 2014; Walz et al, 2014). Variants in the MYC upstream region contribute to inherited susceptibility to most major forms of human cancer, and account for a very large number of cancer cases at the population level (Amundadottir et al, 2006; Gudmundsson et al, 2007; Yeager et al, 2007; Al Olama et al, 2009; Yeager et al, 2009). The polymorphism rs6983267 linked to colorectal (Tomlinson et al, 2007) and prostate (Yeager et al, 2007) cancers contributes more to cancer morbidity and mortality than any other
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