MYC proto-oncogene promoter and 8q24 distal regulatory elements (MYC promoter/8q24 loci)

The MYC promoter and the 8q24 gene desert DNA loci are essential genomic regions that control the expression of the MYC proto-oncogene, a central driver of cell growth, proliferation, and metabolism (Sur and Taipale, 2016, Nature Reviews Cancer). The 8q24 region is a vast "gene desert" containing multiple tissue-specific super-enhancers that physically interact with the MYC promoter through long-range chromatin looping to modulate its activity (Hnisz et al., 2013, Cell). Within the MYC promoter, the Nuclease Hypersensitive Element III1 (NHE III1) can form secondary DNA structures known as G-quadruplexes, which act as silencers of transcription when stabilized (Brooks et al., 2010, Journal of Clinical Oncology). In many cancers, these loci are hijacked through genomic rearrangements or amplification, leading to the constitutive overexpression of MYC and subsequent oncogenic transformation. Therapeutic targeting of these DNA loci involves small molecules designed to stabilize G-quadruplexes or disrupt the epigenetic landscape of the 8q24 enhancers, thereby reducing MYC output (Siddiqui-Jain et al., 2002, PNAS). However, the ubiquitous requirement for MYC in normal regenerative tissues, such as the bone marrow and intestinal epithelium, poses a significant challenge for achieving a wide therapeutic window.

Other names

8q24 gene desertMYC super-enhancersMYC G-quadruplex DNAC-MYC promoterNHE III1 regionMYC island

Stabilization of G-quadruplex structures within the promoter to inhibit transcriptional initiation and disruption of long-range enhancer-promoter interactions.