Typical Enhancers, Super-Enhancers, and Cancers

Abstract

Non-coding segments of the human genome are enriched in cis-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the “archetype” gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity, and the epigenomic features of the chromatin microenvironment across which these regulatory elements reside. Here, we comprehensively describe: fundamental mechanisms of gene expression dysregulation in cancers that involve genomic abnormalities within enhancers’ and Super-enhancers’ (SEs) sequences, which alter the expression of oncogenic transcription factors (TFs); cutting-edge technologies applied for the analysis of variation-enriched hotspots of the cancer genome; and pharmacological approaches for the treatment of Super-enhancers’ aberrant function. Finally, we provide an intratumor meta-analysis, which highlights that genomic variations in transcription-factor-driven tumors are accompanied overexpression of genes, a portion of which encodes for additional cancer-related transcription factors.

EPAS1, a hypoxia‐ and ferroptosis‐related gene, promotes malignant behaviour of cervical cancer by ceRNA and super‐enhancer

“…The differences between super-enhancers and ordinary enhancers are as follows: (1) Super-enhancers are highly modified by H3K27ac and H3K4me1 and bind mediator complexes to the BRD4 protein. [35][36][37] Many key oncogenes in tumour cells are driven by super-enhancers, which play a key role in the development of tumours. 37,38 As a result, super-enhancers have diversified regulation of target genes, such as promoting mRNA generation, miRNA transcription and maturation and lncRNA transcription, among others.…”

“…(5) Super‐enhancers can bind specific transcription factors in tissues. (6) Compared with normal enhancers, blocking transcription factors are more sensitive to the effect of super‐enhancer activity 35–37 . Many key oncogenes in tumour cells are driven by super‐enhancers, which play a key role in the development of tumours 37,38 .…”

“…(6) Compared with normal enhancers, blocking transcription factors are more sensitive to the effect of super‐enhancer activity. 35 , 36 , 37 Many key oncogenes in tumour cells are driven by super‐enhancers, which play a key role in the development of tumours. 37 , 38 As a result, super‐enhancers have diversified regulation of target genes, such as promoting mRNA generation, miRNA transcription and maturation and lncRNA transcription, among others.…”

“… 35 , 36 , 37 Many key oncogenes in tumour cells are driven by super‐enhancers, which play a key role in the development of tumours. 37 , 38 As a result, super‐enhancers have diversified regulation of target genes, such as promoting mRNA generation, miRNA transcription and maturation and lncRNA transcription, among others. Meanwhile, eRNA generated by super‐enhancers also plays a synergistic role in their activity.…”

Germlinecisvariant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)

“…Therapeutic resistance has been reported for nearly all anti-cancer drugs [1], and as many as 90% of mortalities in cancer can be linked to drug resistance [2]. Enhancer-mediated regulation of gene expression has been increasingly implicated in multiple cancer-related processes, including resistance, response, and toxicity to cancer therapies [3, 4]. However, the specific molecular mechanisms through which epigenetic changes drive these processes remain mostly elusive.…”