Super-enhancers in cancer

Abstract

Cancer is fueled by the aberrant activity of oncogenic and tumor suppressive pathways. Transcriptional dysregulation of these pathways play a major role both in the genesis and development of cancer. Dysregulation of transcriptional programs can be mediated by genetic and epigenetic alterations targeting both protein coding genes and non-coding regulatory elements like enhancers and super-enhancers. Super-enhancers, characterized as large clusters of enhancers in close proximity, have been identified as essential oncogenic drivers required for the maintenance of cancer cell identity. As a result, cancer cells are often addicted to the super-enhancer driven transcriptional programs. Furthermore, pharmacological inhibitors targeting key components of super-enhancer assembly and activation have shown great promise in reducing tumor growth and proliferation in several pre-clinical tumor models. This article reviews the current understanding of super-enhancer assembly and activation, the different mechanisms by which cancer cells acquire oncogenic super-enhancers and, finally, the potential of targeting super-enhancers as future therapeutics.

Keywords: 3D chromatin architecture; Cancer; Enhancer hijacking; Genetic variants; Super-enhancers; Transcriptional inhibitors.