Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets

Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regul...

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Bibliographic Details
Published in:Cancer and metastasis reviews 2023-06, Vol.42 (2), p.471-480
Main Authors: Bacabac, Megan, Xu, Wei
Format: Article
Language:English
Subjects:
Acetylation
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Chromatin
Development and progression
DNA binding proteins
Enhancer Elements, Genetic
Enhancers
Epigenetic inheritance
Epigenetics
Gene expression
Genes
Genetic aspects
Genetic transcription
Health aspects
Histones
Humans
Metastases
Metastasis
Neoplasms - genetics
Neoplasms - therapy
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Oncogenes
Oncology
Regulatory sequences
Solid tumors
Targeted cancer therapy
Therapeutic applications
Therapeutic targets
Transcription factors
Transcription Factors - genetics
Tumorigenesis
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Summary:Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regulatory elements and trans-acting factors. Large clusters of enhancers known as “super-enhancers” drive robust expression of cell-fate determining transcription factors in cell identity. Cancer cells can take advantage of super-enhancers and become transcriptionally addicted to them leading to tumorigenesis and metastasis. Additionally, the cis-regulatory landscape of cancer includes aberrant super-enhancers that are not present in normal cells. The landscape of super-enhancers in cancer is characterized by high levels of histone H3K27 acetylation and bromodomain-containing protein 4 (BRD4), and Mediator complex. These chromatin features facilitate the identification of cancer type-specific and cell-type-specific super-enhancers that control the expression of important oncogenes to stimulate their growth. Disruption of super-enhancers via inhibiting BRD4 or other epigenetic proteins is a potential therapeutic option. Here, we will describe the discovery of super-enhancers and their unique characteristics compared to typical enhancers. Then, we will highlight how super-enhancer-associated genes contribute to cancer progression in different solid tumor types. Lastly, we will cover therapeutic targets and their epigenetic modulators.
ISSN:0167-7659
1573-7233
DOI:10.1007/s10555-023-10103-4