An Epigenetic LINE-1-Based Mechanism in Cancer

Int J Mol Sci. 2022 Nov 23;23(23):14610. doi: 10.3390/ijms232314610.

Abstract

In the last fifty years, large efforts have been deployed in basic research, clinical oncology, and clinical trials, yielding an enormous amount of information regarding the molecular mechanisms of cancer and the design of effective therapies. The knowledge that has accumulated underpins the complexity, multifactoriality, and heterogeneity of cancer, disclosing novel landscapes in cancer biology with a key role of genome plasticity. Here, we propose that cancer onset and progression are determined by a stress-responsive epigenetic mechanism, resulting from the convergence of upregulation of LINE-1 (long interspersed nuclear element 1), the largest family of human retrotransposons, genome damage, nuclear lamina fragmentation, chromatin remodeling, genome reprogramming, and autophagy activation. The upregulated expression of LINE-1 retrotransposons and their protein products plays a key role in these processes, yielding an increased plasticity of the nuclear architecture with the ensuing reprogramming of global gene expression, including the reactivation of embryonic transcription profiles. Cancer phenotypes would thus emerge as a consequence of the unscheduled reactivation of embryonic gene expression patterns in an inappropriate context, triggering de-differentiation and aberrant proliferation in differentiated cells. Depending on the intensity of the stressing stimuli and the level of LINE-1 response, diverse degrees of malignity would be generated.

Keywords: LINE-1 retrotransposons; RT inhibitors; autophagy; cancer genesis and progression; chromatin; embryogenesis; genome expression; nuclear lamina; reverse transcriptase (RT).

Publication types

  • Review

MeSH terms

  • Cell Differentiation / genetics
  • Epigenesis, Genetic
  • Humans
  • Long Interspersed Nucleotide Elements* / genetics
  • Neoplasms* / genetics
  • Retroelements

Substances

  • Retroelements