Transcriptional dysregulation by aberrant enhancer activation and rewiring in cancer

Cell identity is controlled by regulatory elements, such as promoters, enhancers, and insulators, within the genome. These regulatory elements interact in the nucleus and form tissue‐specific chromatin structures. Dysregulation of these elements and their interactions can lead to loss of cell identity and promote the development of diseases such as cancer. Tumor cells acquire aberrantly activated enhancers at oncogenic driver genes through various mechanisms. Small genomic changes such as mutations, insertions, and amplifications can form aberrant enhancers. Genomic rearrangements at the chromosomal level, including translocations and inversions, are also often observed in cancers. These rearrangements can result in repositioning of enhancers to locations near tumor‐type‐specific oncogenes. Chromatin structural changes caused by genomic or epigenomic changes lead to mis‐interaction between enhancers and proto‐oncogenes, ultimately contributing to tumorigenesis through activation of oncogenic signals. Additional epigenomic mechanisms can also cause aberrant enhancer activation, including those associated with overexpression of oncogenic transcription factors and the mutation of transcriptional cofactors. Exogenous viral DNA can also lead to enhancer aberrations. Here, we review the mechanisms underlying aberrant oncogene activation through enhancer activation and rewiring, both of which are caused by genomic or epigenomic alterations in non‐coding regions. Chromatin structural changes caused by genomic changes, including mutations, insertions, amplifications, or chromosomal translocations and inversions, lead to mis‐interaction between enhancers and proto‐oncogenes, ultimately contributing to tumorigenesis through activation of oncogenic signals. Epigenomic mechanisms can also cause aberrant enhancer activation, including those associated with overexpression of oncogenic transcription factors and the mutation of transcriptional cofactors. Here, we review these tumorigenic mechanisms through aberrant enhancer activation and rewiring that should help to understand how genomic or epigenomic alterations in non‐coding regions can contribute to cancer development.