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.

Bibliometric analysis of evolutionary trends and hotspots of super-enhancers in cancer

“…As we discussed above, SEs and regulated genes play important roles in the biological process of cancer cells, and therapy targeting SEs is a promising cancer treatment strategy. Recent research focuses on developing small molecule inhibitors targeting SE components, especially BRD4 and CDK7 inhibitors (Xiang-Ping Li et al, 2023). Pre-clinical studies and undergoing clinical trials showed significant antitumor efficacy of these inhibitors.…”

“…Pre-clinical studies and undergoing clinical trials showed significant antitumor efficacy of these inhibitors. However, limited clinical applications of inhibitors are available because of significant toxicity and adverse events (Xiang-Ping Li et al, 2023). It has been demonstrated in a study that the BRD4/LSD1/NuRD complex is destroyed by the BRD4 inhibitor JQ1 when used for a long period, leading to resistance to JQ1 and a broad spectrum of antitumor compounds (Liu et al, 2022).…”

“…seRNAs regulate multiple tumors' malignant progression (Peng et al, 2019;Tan et al, 2020). Moreover, seRNAs promote transcription by enhancing the formation of SE-gene promoter loops (Wu and Shen, 2019;Xiang-Ping Li et al, 2023). Diverse TFs and coactivators (such as BRD4 and MED1) may enrich the SEs and form phase-separated condensates to drive oncogene expression (Sabari and Dall'Agnese, 2018;Boija et al, 2018).…”

Pan-cancer analysis of super-enhancer-induced LINC00862 and validation as a SIRT1-promoting factor in cervical cancer and gastric cancer

“…In particular, many lncRNAs have been identified as novel biomarkers for immunotherapy [ 12 , 13 ]. Super-enhancer-related genes are closely related with many tumor characteristics such as immune response [ 14 ]. Recently, super-enhancer-related lncRNAs (SE-lncRNAs) are emerging as new biomarkers for predicting immunotherapy efficacy [ 15 ].…”