EPIGENETIC DYSREGULATION OF TRANSPOSABLE ELEMENTS IN CANCER AND THEIR ROLES IN TUMOR PROGRESSION, IMMUNE REMODELING, AND THERAPEUTIC TARGETING

Abstract

Transposable elements (TEs) make up approximately half of the human genome and have recently been identified as key gene expression and tumorigenesis regulators․ In healthy cells‚ TEs are silenced and repressed by diverse epigenetic mechanisms‚ such as DNA methylation‚ histone modifications‚ chromatin remodeling complexes‚ and non-coding RNA․ In cancer‚ perturbations in regulation are induced by epigenetic instability‚ a tissue-wide destabilization of the epigenetic landscape of a genome‚ leading to a global loss of DNA methylation‚ heterochromatin loss‚ chromatin remodeling and TE activation․ TE activity contributes to tumorigenesis by insertional mutagenesis‚ generating genomic instability‚ and modulating gene expression using TE-derived promoters and enhancers․ TE-derived nucleic acids (e․g․ double-stranded RNA) also trigger natural immune sensing pathways (such as cGAS-STING and MDA5-MAVS) to initiate antiviral-type interferon responses that can improve anti-tumor immunity․ However‚ chronic TE RNA-induced interferon signaling may also promote immune escape through ADAR1-mediated RNA editing of TE-derived RNAs and immunosuppressive changes in the tumor microenvironment (TME)․ The involvement of TE activity in stromal reprogramming‚ immune dysregulation‚ and three-dimensional genome reorganization within the tumor ecosystem has been increasingly supported․ TEs are now considered to play important roles in epigenetic dysregulation and immune response dysregulation and as potential therapeutic targets․ Efforts to develop anti-TE-based therapeutics are being pursued using epigenetic drugs‚ immune checkpoint inhibitors‚ and CRISPR-based epigenome editing․