Super-enhancer complexes regulating MYC transcription (MYC-SE complexes)

Super-enhancer complexes regulating MYC transcription are large clusters of transcriptional enhancers that drive exceptionally high levels of the MYC oncogene expression in various cancers (Hnisz et al., 2013, Cell). These complexes are characterized by a high density of transcription factors, co-activators like the Mediator complex (MED1), and epigenetic readers such as Bromodomain-containing protein 4 (BRD4) (Loven et al., 2013, Cell). In many malignancies, chromosomal rearrangements or focal amplifications create or hijack these super-enhancers to sustain the addiction of cancer cells to MYC-driven proliferative signals (Bradner et al., 2017, Cell). Because super-enhancers are disproportionately sensitive to the disruption of transcriptional machinery compared to typical enhancers, they represent a vulnerable therapeutic target. Pharmacological intervention typically involves small molecules that inhibit BET proteins, cyclin-dependent kinases like CDK7 or CDK9, or p300/CBP acetyltransferases (Kwiatkowski et al., 2014, Nature). These drugs work by disrupting the recruitment of the transcriptional apparatus or preventing the phosphorylation of RNA polymerase II, leading to a rapid collapse of MYC expression. While targeting these complexes shows significant preclinical and clinical promise in hematologic and solid tumors, challenges include dose-limiting toxicities such as thrombocytopenia. Additionally, the development of compensatory resistance mechanisms, such as the use of alternative enhancers, remains a significant hurdle in clinical settings (Ott et al., 2018, Cancer Cell).

Other names

MYC super-enhancersMYC-associated super-enhancer complexesMYC-SEMYC-regulating super-enhancersMYC-driven super-enhancer clusters

Disruption of the transcriptional machinery at super-enhancer regions through the inhibition of BET proteins (e.g., BRD4), which prevents the recruitment of co-activators, or the inhibition of transcriptional kinases (e.g., CDK7, CDK9) to block RNA polymerase II initiation and elongation (Loven et al., 2013, Cell; Kwiatkowski et al., 2014, Nature).