Super-enhancers in hepatocellular carcinoma: regulatory mechanism and therapeutic targets

Abstract

Super-enhancers (SEs) represent a distinct category of cis-regulatory elements notable for their robust transcriptional activation capabilities. In tumor cells, SEs intricately regulate the expression of oncogenes and pivotal cancer-associated signaling pathways, offering significant potential for cancer treatment. However, few studies have systematically discussed the crucial role of SEs in hepatocellular carcinoma (HCC), which is one of the most common liver cancers with late-stage diagnosis and limited treatment methods for advanced disease. Herein, we first summarize the identification methods and the intricate processes of formation and organization of super-enhancers. Subsequently, we delve into the roles and molecular mechanisms of SEs within the framework of HCC. Finally, we discuss the inhibitors targeting the key SE-components and their potential effects on the treatment of HCC. In conclusion, this review meticulously encapsulates the distinctive characteristics of SEs and underscores their pivotal roles in the context of hepatocellular carcinoma, presenting a novel perspective on the potential of super-enhancers as emerging therapeutic targets for HCC.

Keywords: Hepatocellular carcinoma; Super-enhancer; Therapeutic targets.

Fig. 1

The difference between typical enhancers and super-enhancers

Fig. 2

The specific process of SE identification and advanced techniques

Fig. 3

Super-enhancers recruit transcription complexes and form 3D structures. (A) Pioneer factors bind to closed chromatin with a high level of H3K9me2 and transform it into “primed enhancers” characterized by H3K4me1. Through the recruitment of CBP/P300, primed enhancers can get H3K27ac at nucleosomes and become active enhancers. Finally, the histone “reader” BRD4 binds to the active enhancers and recruits Med1 and RNA pol II, which form transcription complexes at the SE region. (B) Compartments - Topologically associating domains” model of super-enhancers. The IDR of BRD4 and MED1 mediate the formation of phase-separated and promote compartment formation. The CTCF and cohesion promote the process of loop-extrusion and determine the TAD boundaries

Fig. 4

The roles and molecular mechanisms of super-enhancers in HCC