Super-enhancers and novel therapeutic targets in colorectal cancer

Qian Liu,Jimin Shao,Zhiyuan Lou,Lijuan Guo,Xueping Xiang

doi:10.1038/s41419-022-04673-4

Abstract

Transcription factors, cofactors, chromatin regulators, and transcription apparatuses interact with transcriptional regulatory elements, including promoters, enhancers, and super-enhancers (SEs), to coordinately regulate the transcription of target genes and thereby control cell behaviors. Among these transcriptional regulatory components and related elements, SEs often play a central role in determining cell identity and tumor initiation and progression. Therefore, oncogenic SEs, which are generated within cancer cells in oncogenes and other genes important in tumor pathogenesis, have emerged as attractive targets for novel cancer therapeutic strategies in recent years. Herein, we review the identification, formation and activation modes, and regulatory mechanisms for downstream genes and pathways of oncogenic SEs. We also review the therapeutic strategies and compounds targeting oncogenic SEs in colorectal cancer and other malignancies.

Highlights

Colorectal cancer (CRC) is a malignancy with high morbidity and mortality worldwide [1, 2]
The researchers created a catalog of SEs and their associated genes in a broad spectrum of human cell and tissue types, showed that disease-associated variations were especially enriched in the SEs of disease-relevant cell types, and importantly, proposed that cancer cells generally acquired SEs at oncogenes and other genes that play important roles in cancer pathogenesis
The single-nucleotide polymorphisms (SNPs) rs6854845 in an SE destroys the review, using CRC as an example, we summarize the identification distant interaction between the SE and targeted gene clusters, approaches, architecture, activation mechanisms, downstream affecting the transcription of these genes, which play important genes, and related pathogenic pathways of oncogenic SEs, as well roles in colon cell growth and inflammatory responses [57]

Summary

Introduction

Colorectal cancer (CRC) is a malignancy with high morbidity and mortality worldwide [1, 2]. There are diverse underlying pathogenic mechanisms in CRC, including somatic mutations, genetic instability, gene fusions, and epigenetic alterations [3–5]. The high death rate of CRC patients is mainly attributed to the high rate of metastasis and recurrence and the shortage of novel effective therapies [6]. Further clarification of disease mechanisms and development of novel potent therapeutics are still urgently needed tasks for efficient CRC treatment. Gene transcription is a complex and highly coordinated process. Transcription factors (TFs), cofactors, chromatin regulators, RNA polymerase II (Pol II), and related transcriptional machinery directly or indirectly bind to transcriptional regulatory elements, including promoters, enhancers and super-enhancers (SEs), thereby regulating the expression of target genes [7–11]. In 2013, Young and colleagues used the term ‘super-enhancers’ to describe large clusters of enhancers that drive the transcriptional expression of genes that define cell identity [12–14]. The researchers created a catalog of SEs and their associated genes in a broad spectrum of human cell and tissue types, showed that disease-associated variations were especially enriched in the SEs of disease-relevant cell types, and importantly, proposed that cancer cells generally acquired SEs at oncogenes and other genes that play important roles in cancer pathogenesis

Methods

Conclusion