Deregulation of Transcriptional Enhancers in Cancer

SIMPLE SUMMARY: One of the major challenges in cancer treatments is the dynamic adaptation of tumor cells to cancer therapies. In this regard, tumor cells can modify their response to environmental cues without altering their DNA sequence. This cell plasticity enables cells to undergo morphological and functional changes, for example, during the process of tumour metastasis or when acquiring resistance to cancer therapies. Central to cell plasticity, are the dynamic changes in gene expression that are controlled by a set of molecular switches called enhancers. Enhancers are DNA elements that determine when, where and to what extent genes should be switched on and off. Thus, defects in enhancer function can disrupt the gene expression program and can lead to tumour formation. Here, we review how enhancers control the activity of cancer-associated genes and how defects in these regulatory elements contribute to cell plasticity in cancer. Understanding enhancer (de)regulation can provide new strategies for modulating cell plasticity in tumour cells and can open new research avenues for cancer therapy. ABSTRACT: Epigenetic regulations can shape a cell’s identity by reversible modifications of the chromatin that ultimately control gene expression in response to internal and external cues. In this review, we first discuss the concept of cell plasticity in cancer, a process that is directly controlled by epigenetic mechanisms, with a particular focus on transcriptional enhancers as the cornerstone of epigenetic regulation. In the second part, we discuss mechanisms of enhancer deregulation in adult stem cells and epithelial-to-mesenchymal transition (EMT), as two paradigms of cell plasticity that are dependent on epigenetic regulation and serve as major sources of tumour heterogeneity. Finally, we review how genetic variations at enhancers and their epigenetic modifiers contribute to tumourigenesis, and we highlight examples of cancer drugs that target epigenetic modifications at enhancers.