The emergence and progression of cancers is accompanied by a dysregulation of transcriptional programs. The three-dimensional (3D) organization of the human genome has emerged as an important multi-level mediator of gene transcription and regulation. In cancer cells, this organization can be restructured, providing a framework for the deregulation of gene activity. The CTCF protein, initially identified as the product from a tumor suppressor gene, is a jack-of-all-trades for the formation of 3D genome organization in normal cells. Here, we summarize how CTCF is involved in the multi-level organization of the human genome and we discuss emerging insights into how perturbed CTCF function and DNA binding causes the activation of oncogenes in cancer cells, mostly through a process of enhancer hijacking. Moreover, we highlight non-canonical functions of CTCF that can be relevant for the emergence of cancers as well. Finally, we provide guidelines for the computational identification of perturbed CTCF binding and reorganized 3D genome structure in cancer cells.
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