Enhancer regulation in cancer: from epigenetics to m6A RNA modification

Enhancers are crucial cis-regulatory DNA elements that regulate gene transcription by interacting with promoters, often over long genomic distances. Unlike promoters, their activity is independent of orientation or proximity to the gene. Active enhancers are transcribed into non-coding enhancer RNAs (eRNAs), which help stabilize enhancer-promoter loops, recruit transcription machinery, and shape the chromatin architecture. These eRNAs are regulated post-transcriptionally, through modifications such as the N6-methyladenosine (m⁶A) modification, which enhances their stability, facilitates interactions with nuclear reader proteins, and supports transcriptional condensate formation, thereby boosting enhancer activity. Super-enhancers, clusters of strong enhancers marked by high levels of modified H3 histone protein, acetylated at lysine 27, generate abundant eRNAs and are key drivers of gene expression in development and cancer. This review offers a comprehensive overview of the structure and function of enhancers and super-enhancers, highlights their regulatory roles, and examines the emerging contribution of m⁶A RNA modification in enhancer-mediated transcription during carcinogenesis. Additionally, we discuss experimental approaches for studying enhancer activity and explore potential therapeutic strategies targeting enhancer-associated pathways in cancer. By integrating recent advances in enhancer research, we aim to shed light on the intricate molecular choreography that orchestrates gene expression and its dysregulation in cancer.