Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

Cancer heterogeneity arises during tumor progression as a consequence of genetic insults, environmental cues, and reversible changes in the epigenetic state, favoring tumor cell plasticity. The role of enhancer reprogramming is emerging as a relevant field in cancer biology as it supports adaptation of cancer cells to those environmental changes encountered during tumor progression and metastasis seeding. In this review, we describe the cancer-related alterations that drive oncogenic enhancer activity, leading to dysregulated transcriptional programs. We discuss the molecular mechanisms of both cis- and trans-factors in overriding the regulatory circuits that maintain cell-type specificity and imposing an alternative, de-regulated enhancer activity in cancer cells. We further comment on the increasing evidence which implicates stress response and aging-signaling pathways in the enhancer landscape reprogramming during tumorigenesis. Finally, we focus on the potential therapeutic implications of these enhancer-mediated subverted transcriptional programs, putting particular emphasis on the lack of information regarding tumor progression and the metastatic outgrowth, which still remain the major cause of mortality related to cancer.