Decoding the crosstalk between extrachromosomal DNA and super-enhancers: new frontiers in cancer epigenetics

Extrachromosomal DNA (ecDNA) has emerged as a crucial DNA regulatory element in the biological and medical fields because of its distinct topology and genetic attributes. This DNA exists independently of conventional chromosomes. The unique distribution patterns of ecDNA make it a valuable potential biomarker for various ailments, especially cancer. A deeper understanding of ecDNA could pave the way for novel approaches to targeted cancer therapy. Super-enhancers (SEs), powerful chromatin regulatory elements characterized by high densities of transcription factors and specific histone modifications, play pivotal roles in driving oncogene expression and maintaining cancer cell identity. In tumor cells, ecDNA can act as a super-enhancer to modulate gene expression, and influence tumor formation, advancement, and heterogeneity. The ability of ecDNA to function as a mobile enhancer has been recognized; however, the underlying molecular mechanisms and its functional crosstalk with SEs remain underexplored. This review provides a thorough analysis of the structure, formation processes, and functions of ecDNA, focusing on its super-enhancer-like features, interactions with SEs, and role in tumor biology. We also evaluate the clinical implications of targeting ecDNA-driven transcriptional programs in cancer therapy.