Epigenetic dysregulation of retrotransposons in cancer

Abstract Approximately 97% of the human genome comprises non-coding sequences, with nearly half originating from transposable elements. Among these, retrotransposons represent a critical subclass that replicates via a "copy-and-paste" mechanism and significantly influences the regulation of host genomes. In both normal and pathological contexts, retrotransposons contribute a vast reservoir of regulatory elements that can modulate the expression of genes. If left unchecked, retrotransposons can substantially affect host transcriptional programs and genomic integrity. Therefore, various mechanisms, including epigenetic modifications, are employed to mitigate their potentially deleterious effects. In diseases such as cancers, the epigenome is often significantly reprogrammed, which can lead to retrotransposon dysregulation. Drawing insights from recent studies conducted in human and murine cells, this review examines how retrotransposons expand the complexity of mammalian genomes, describes the impact of their epigenetic dysregulation in cancer development, and highlights the potential of targeting these sequences for therapeutic strategies.