The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors

Abstract

Digestive system tumors include malignancies of the stomach, pancreas, colon, rectum, and the esophagus, and are associated with high morbidity and mortality. Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. The aberrant transcription of key oncogenes is driven by super-enhancers (SEs), which are characterized by large clusters of enhancers with significantly high density of transcription factors, cofactors, and epigenetic modulatory proteins. The SEs consist of critical epigenetic regulatory elements, which modulate the biological characteristics of digestive system tumors including tumor cell identity and differentiation, tumorigenesis, environmental response, immune response, and chemotherapeutic resistance. The core transcription regulatory loop of the digestive system tumors is complex and a high density of transcription regulatory complexes in the SEs and the crosstalk between SEs and the noncoding RNAs. In this review, we summarized the known characteristics and functions of the SEs in the digestive system tumors. Furthermore, we discuss the oncogenic roles and regulatory mechanisms of SEs in the digestive system tumors. We highlight the role of SE-driven genes, enhancer RNAs (eRNAs), lncRNAs, and miRNAs in the digestive system tumor growth and progression. Finally, we discuss clinical significance of the CRISPR-Cas9 gene editing system and inhibitors of SE-related proteins such as BET and CDK7 as potential cancer therapeutics.

Keywords: digestive system tumors; non-coding RNAs; super-enhancer; therapeutic targets.; tumor progression.

Figure 1

Characteristics of SEs. (A) Compared with the typical enhancers, super-enhancer regions are occupied by a higher density of transcription-related factors including transcription factors (TFs), co-activators, mediators, and RNA pol II complexes. (B) The core transcriptional circuit consists of several auto-regulated TFs and TF-related SEs, which are assembled into interconnected loops to coordinate the expression of cell identity- and tumor-related genes. (C) The enhancer RNAs (eRNAs) generated by the transcription of SE regions mediate chromatin looping between the SE and gene promoter sequences. The eRNAs induce formation and stabilization of the chromatin loop between SE and gene promoters by recruiting RNA Pol II, co-factors, and mediators. The eRNAs also assist in the promoter-enhancer circularization through cohesins. (D) The phase separation model of SE activation demosntrates high-density interactions between transcriptional regulatory factors that form distinct multi-molecular complexes in the SE region and drive the transcription of SE-associated genes. Note: E, enhancer; P, promoter; G, target gene; TF, transcription factor; CoF, cofactor; Med, mediator.

Figure 2

Schematic representation of the mechanisms and biological functions of SEs in the five main solid tumors of the digestive system. SE-related TFs and SE-target gene promoter loops regulate the expression of oncogenes or tumor suppressor genes and promote malignant proliferation, migration, invasion, metastasis, and recurrence of the digestive system tumors. Note: ESCC, esophageal squamous cell carcinoma; GC, gastric cancer; CRC, colorectal cancer; HCC, hepatocellular carcinoma; PDAC, pancreatic ductal adenocarcinoma.

Figure 3

The known oncogenic SE-targeting small molecule inhibitors and gene-editing mechanisms. BET inhibitors such as JQ1, iBET-762, iBET-151, and ABBV-774 suppress transcription of oncogenes by either binding to the BET bromodomains or displacing the BET bromodomains. Thus, the interactions between BRD4 and the acetylated sites in the SE region are blocked. CDK7 inhibitors such as THZ1 and THZ2 inhibit the transcription of SE-associated oncogenes by binding covalently to CDK7 and reduce the phosphorylation of the RNA pol II C-terminal domain. CRISPR-Cas9 gene-editing system modulates SE-induced oncogene transcription by remodeling the epigenetic landscapes at the sgRNA-targeted enhancers and associated genes. Gene editing is a convenient tool to analyze the functions of SEs and discover new targets for cancer treatment. Note: TF, transcription factor; H3K27ac, acetylation of histone 3 lysine 27; P, phosphate group; RNA pol II, RNA polymerase II.