The molecular understanding of super-enhancer dysregulation in cancer

Abstract

Abnormalities in the regulation of gene expression are associated with various pathological conditions. Among the distal regulatory elements in the genome, the activation of target genes by enhancers plays a central role in the formation of cell type-specific gene expression patterns. Super-enhancers are a subclass of enhancers that frequently contain multiple enhancer-like elements and are characterized by dense binding of master transcription factors and Mediator complexes and high signals of active histone marks. Super-enhancers have been studied in detail as important regulatory regions that control cell identity and contribute to the pathogenesis of diverse diseases. In cancer, super-enhancers have multifaceted roles by activating various oncogenes and other cancer-related genes and shaping characteristic gene expression patterns in cancer cells. Alterations in super-enhancer activities in cancer involve multiple mechanisms, including the dysregulation of transcription factors and the super-enhancer-associated genomic abnormalities. The study of super-enhancers could contribute to the identification of effective biomarkers and the development of cancer therapeutics targeting transcriptional addiction. In this review, we summarize the roles of super-enhancers in cancer biology, with a particular focus on hematopoietic malignancies, in which multiple super-enhancer alteration mechanisms have been reported.

Keywords: cancer therapy; genome; oncogene; super-enhancer; transcription factor.

Fig. 1

Comparison of typical enhancers and super-enhancers Super-enhancers are enriched with more transcription factors, Mediator complexes, and RNA Pol II molecules than typical enhancers. Hence, super-enhancers have higher transcription activity levels than typical enhancers. Super-enhancers activate cell identity–related gene expression programs. TF: transcription factor Pol II: RNA polymerase II

Fig. 2

Dysregulation of super-enhancers by abnormalities in transcription factors and transcriptional regulators Abnormalities in transcriptional regulators reported in hematological malignancies are categorized as a combination of mechanisms, including (1) production of chimeric TFs, (2) altered expression, function, and stability of transcriptional regulators, and (3) altered crosstalk among various transcriptional regulators. Abnormalities in transcriptional regulators result in dysregulation of super-enhancers observed in normal cells (black) and/or formation of novel super-enhancer near oncogenes (red).

Fig. 3

Dysregulation of super-enhancers by genomic aberrations Fig. 3A: Translocations, inversions, and interchromosomal deletions rearrange the positional relationships between super-enhancers and proto-oncogenes, leading to abnormal transcription and cancer development. Fig. 3B–3C: Other mechanisms include focal amplifications of super-enhancer regions (B), point mutation, or small insertions or deletions (indels) that create new super-enhancers (C). These mechanisms can also increase transcriptional output and perturb the regulation of oncogenes.

Fig. 4

Therapeutic targeting of super-enhancers in cancers The discovery of JQ1 and other bromodomain inhibitors, as well as the preferential targeting of super-enhancers, has led to the development of several first- and second-generation bromodomain inhibitors. CDK7 (CDK12/CDK13) is also attracting attention as a target for cancer therapy; CDK7 inhibitors have been reported to be effective against various types of cancer. BETi: bromodomain and extraterminal domain inhibitor