Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets

Abstract

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.

Keywords: BRD4; Enhancer reprogramming; Epigenetic modulators; Mediator; Metastasis; Super-enhancers.

Fig. 1

Cancer cells can acquire super-enhancers at oncogenes. In normal cells, typical enhancers (TEs) express a proto-oncogene at normal levels. There is a moderate amount of H3K27ac, histone acetyltransferases (HATs), BRD4, Mediator, transcription factors, and Pol II. Cancer cells can reorganize chromatin to form super-enhancers (SEs) at proto-oncogenes. The enhancerpromoter contact is stabilized by CTCF and cohesin binding. These super-enhancers contain the same components as TEs, but at much higher levels. The increased amount of transcriptional machinery leads to robust transcription and promotes oncogenic expression

Fig. 2

Super-enhancers can mediate cancer metastasis. A BRD4 can interact with NF-κB p65 and Med1 subunit of Mediator to promote transcription of cancer stemness genes. B The SWI/SNF complex can recruit BRD4 to SEs to drive transcription of oncogenes. C In a normal pancreatic cell, KDM6A dictates where the COMPASS-like complex binds and regulates enhancer demarcation. When KDM6A is lost, the localization of the COMPASS-like complex changes and leads to the activation of super-enhancers regulating genes that drive squamous differentiation and metastasis

Fig. 3

Epigenetic modulators and other drugs targeting SEs. AU-15330 degrades SWI/SNF, keeping chromatin in a closed conformation. CARM1 inhibitor treatment inhibits methylation of BAF155, preventing proper recruitment of BRD4. HDAC inhibition affects acetylation mark levels, interfering with proper SE to promoter interactions. CBP30 and ICG-001 inhibit the histone acetyltransferase activity of CBP/p300. JQ1 and I-BET directly target BRD4. SKLB325 targets the coactivator function of JMJD6. THZ1 and THZ2 inhibit CDK7, preventing phosphorylation of Pol II