Typical Enhancers, Super-Enhancers, and Cancers

SIMPLE SUMMARY: The cancer genome has been exhaustively studied upon the advent of Next-Generation Sequencing technologies. Coding and non-coding sequences have been defined as hotspots of genomic variations that affect the naïve gene expression programs established in normal cells, thus working as endogenous drivers of carcinogenesis. In this review, we comprehensively summarize fundamental aspects of gene expression regulation, with emphasis on the impact of sequence and structural variations mapped across non-coding cis-acting elements of genes encoding for tumor-related transcription factors. Chromatin architecture, epigenome reprogramming, transcriptional enhancers and Super-enhancers, oncogene regulation, cutting-edge technologies, and pharmacological treatment are substantially highlighted. 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.