The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer

Abstract

MYC is one of the most important oncogenes in cancer. Indeed, MYC is upregulated in 50–60% of all tumors. MYC overexpression can be achieved through a variety of mechanisms, including gene duplications, chromosomal translocations or somatic mutations leading to increased MYC stability. However, recent studies have identified numerous tissue-specific non-coding enhancers of MYC that play major roles in cancer, highlighting long-range transcriptional regulation of MYC as a critical novel mechanism leading to MYC hyperactivation and as a potential target for new therapeutic strategies in the near future. Here, we summarize the regions and mechanisms involved in the long-range transcriptional regulation of MYC, underscoring the relevance of MYC enhancers both in normal physiological development and in MYC-driven cancer initiation and progression.

Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

“…The reduction in MYC expression is likely to be a significant contributor to the synergy observed in the MLL-r AML given that a BRD4-and CDK9-dependent MYC superenhancer is essential for maintenance of MLL-MLLT3-driven AML in mouse models. 11,19,20 Another report also shows that combining a BET inhibitor with alternative CDK9 inhibitors synergistically repressed MYC in an MLL-AML cell line; however, this was not investigated in primary AML. 21 To define other key myeloid oncogenic drivers, downregulation of which may contribute to the synergistic response, we determined genes that were uniquely downregulated in the combination treatment relative to control, or were downregulated by either single agent and in the combination (supplemental Figure 4A; supplemental Table 3).…”

Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1–AKT axis-mediated glycolysis

“…The pro-oncoprotein c-Myc is upregulated in 50–60% of tumors and functioned in both initiation and progression of the tumor 43 , 44 . However, the functional roles of c-Myc in LSCC are not fully understood.…”

Multi‐omics analysis reveals the functional transcription and potential translation of enhancers

“…56 But in different cancer types, the enhancers that drive MYC overexpression is quite different. 57 In lung cancer, we identified a cluster of 31 transcribed enhancers near MYC locus ( Figure 5D). In Figure 5E), which is in agreement with previous reports in other cancers.…”