Fig. 3: Epigenetic mechanisms of enhancer reprogramming.

A Terminal TFs from multiple signaling pathways bind to specific enhancers to respond to environmental signals. Enhancers contain activating or repressive elements, which are controlled by different TFs. However, in cancer, repressive elements are often silenced, leading to the hyperactivity of activating elements. Mutations in pioneer factors confer non-canonical functions, reshaping enhancer activity and driving cancer progression, therapeutic resistance, and phenotypic transitions. B Histone modifications, regulated by “writer” enzymes such as MLL3, MLL4, CBP, and EZH2, play a crucial role in enhancer activity and gene expression. In cancer, mutations or dysfunctions in these enzymes lead to enhancer reprogramming, promoting oncogene activation and tumor suppressor gene silencing. MLL3/MLL4 mutations impair H3K4me1 deposition, disrupting enhancer function and increasing cancer cell invasiveness. CBP/p300 mutations reduce H3K27ac, suppressing immune-related genes and enhancing oncogenic transcription. Overactive EZH2 catalyzes H3K27me3 deposition, repressing key enhancers and contributing to immune evasion and differentiation blockage. C ATP-dependent chromatin remodeling complexes, such as SWI/SNF, regulate chromatin accessibility by modifying nucleosome positioning, with mutations in their core subunits (e.g., ARID1A, SMARCA4, SMARCA2) frequently observed in cancers. These mutations compromise chromatin remodeling, altering enhancer activity and gene expression. D Disruption and rearrangement of TAD boundaries in cancer enable enhancers to form abnormal interactions with oncogenes, driving their overexpression and promoting tumor progression. E Enhancer fragments carried by ecDNA interact with target gene promoters across the genome, leading to transcriptional reprogramming. (Created with BioRender.com).