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.

Unraveling a novel dual-function regulatory element showing epistatic interaction with a variant that escapes genome-wide association studies

“…It is important to note that the association signal for rs11240391, newly identified here, could not be detected in previous genome-wide association studies, as this SNP is not included among the genotyped variants and is in very low LD with all other SNPs (r 2 < 0.4, except for rs6680886 having an r 2 of 0.56) in African populations. The LD between rs11240391 and the TagSNP rs10900585 associated with severe malaria by GWAS was estimated to be r 2 = 0.0015 in African populations using the LD pair module in LDlink web-based application 38 .…”

“…Gene expression is tightly regulated in time and space to ensure that genes are switched on or off at the right times and in the right amounts. Disruption in this regulation can result in a wide range of diseases and syndromes including cancers 1,2 , neurological 3,4 , developmental disorders, autoimmune, cardiovascular, and infectious diseases 5 . Gene expression profiling has therefore emerged as a powerful approach for gaining deeper insights into the pathological mechanisms of complex diseases by identifying specific transcriptomic signatures linked to these pathologies [6][7][8][9][10][11][12][13] .…”

3C methods in cancer research: recent advances and future prospects

“…Superenhancers (SEs) can also be redirected by enhancer hijacking to promote the expression of oncogenes or other genes that drive tumorigenesis. This aberrant activation of SEs substantially contributes to cancer development and progression 107 , 108 (Fig. 3a ).…”

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

“…Super-enhancers are a cluster of regulatory regions, specifically enhancers, with unusually strong enrichment for the binding of transcriptional coactivators, readers, and transcription factors ( 193 ). Super-enhancers can be essential oncogenic drivers, leading to high expression of many oncogenes ( 194 ). Different families of transcription factors occupy super-enhancer sites; prominently among which is the bromodomain and extraterminal domain (BET) family.…”