Transcriptional regulation by MYC: an emerging new model

The transcription factor MYC has long been recognized for its pivotal role in transcriptional regulation of genes fundamental for cellular processes such as cell cycle, apoptosis, and metabolism. Dysregulation of MYC activity is implicated in various diseases, most notably cancer, where MYC drives uncontrolled cell proliferation and growth. Despite its significant role in cancer biology, targeting MYC for therapeutic purposes has been challenging due to its highly disordered protein structure. Hence, recent research efforts have focused on identifying the transcriptional mechanisms underlying MYC function to identify alternative strategies for intervention. This review summarizes recent advances in our understanding of how MYC orchestrates context-dependent and -independent gene-regulatory activities in cancer. Based on recent insights into the gene-regulatory function of MYC at enhancers, we propose an extension of the gene-specific affinity model. In this revised model, MYC enhancer activity drives context-specific gene programs that are distinct from the ubiquitously activated set of core MYC target genes driven by MYC promoter binding. The increased MYC enhancer activity in cancer and the distinct function of MYC at these regions compared to promoters may provide an opportunity for designing therapeutic approaches selectively targeting MYC enhancer activity in cancer cells.