Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

Abstract

Transcriptional deregulation, a cancer cell hallmark, is driven by epigenetic abnormalities in the majority of brain tumors, including adult glioblastoma and pediatric brain tumors. Epigenetic abnormalities can activate epigenetic regulatory elements to regulate the expression of oncogenes. Superenhancers (SEs), identified as novel epigenetic regulatory elements, are clusters of enhancers with cell-type specificity that can drive the aberrant transcription of oncogenes and promote tumor initiation and progression. As gene regulators, SEs are involved in tumorigenesis in a variety of tumors, including brain tumors. SEs are susceptible to inhibition by their key components, such as bromodomain protein 4 and cyclin-dependent kinase 7, providing new opportunities for antitumor therapy. In this review, we summarized the characteristics and identification, unique organizational structures, and activation mechanisms of SEs in tumors, as well as the clinical applications related to SEs in tumor therapy and prognostication. Based on a review of the literature, we discussed the relationship between SEs and different brain tumors and potential therapeutic targets, focusing on glioblastoma.

Fig. 1. Schematic diagram of the structure and characteristics of SEs.

SEs recruit TFs, mediators, RNA pol II, histone modifiers, and other chromatin regulators, activating the expression of downstream genes. The enhancer-promoter loop that is formed with the help of seRNAs contributes to the transcription of target genes. Blocking SEs with BRD4 or CDK7 inhibitors is considered a viable antitumor approach. SE superenhancer, TF transcription factors, BRD4 bromodomain protein 4, CDK7 cyclin-dependent kinase 7.

Fig. 2. The liquid–liquid phase separation model of SEs.

At the superenhancer locus, transcriptional regulators with extensive interactions, including TFs, BRD4, MED1, RNA pol II, and enhancer RNAs, are enriched to form a phase-separated condensate, which is separated from other chromatin domains and can drive transcriptional bursting and produce simultaneous activation of genes.

Fig. 3. Functional activation mechanisms of oncogenic SEs.

Genetic mutations, single-nucleotide polymorphisms (SNPs), chromosomal rearrangements, and viral infections lead to SE formation and oncogene activation.

Fig. 4. Regulatory mechanisms of oncogenic SEs in glioblastoma (GBM).

a In GBM cells, five highly expressed SE-associated genes are associated with sensitivity to the CDK7 inhibitor THZ1. b Myc and MED1 mediate the epigenetic activation of TMEM44-AS1, which is directly bound to SerpinB3, and sequentially activate Myc and EGR1/IL-6 signaling; Myc induces transcription of TMEM44-AS1 and binds to the SE region, forming a positive feedback loop with TMEM44-AS1, thus aggravating tumor progression c The RFP-HDAC1 complex contributes to TMZ resistance via aberrant deacetylation of H3K27ac, and the disruption of the complex leads to an increase in TMZ efficacy by changing core histone modifications in GBM. d The core transcriptional regulatory circuitry (CRC) in GBM: SE-driven TFs are highly enriched in SE regions and regulate the expression of SE-associated lncRNAs. The BET degrader dBET6 can effectively disrupt the expression of core TFs.