1. TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis
- Author
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Audrey Laurent, Thierry Madigou, Sarah Guimard, Elise A. Mahé, Raphaël Métivier, Maud Bizot, Christine Le Péron, Stéphane Avner, Marion Turpin, Gilles Salbert, Gaëlle Palierne, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was funded by the AVIESAN/Plan Cancer and La Ligue Contre le Cancer. The Genomic Paris Centre facility was supported by the France Génomique national infrastructure, funded as part of the 'Investissements d’Avenir' program managed by the Agence Nationale de la Recherche (contract ANR-10-INBS-0009)., and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
- Subjects
Health, Toxicology and Mutagenesis ,[SDV]Life Sciences [q-bio] ,Breast Neoplasms ,Plant Science ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Dioxygenases ,Epigenesis, Genetic ,Proto-Oncogene Proteins c-myc ,Lysosome ,Proto-Oncogene Proteins ,Gene expression ,medicine ,Humans ,Transcription factor ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Ecology ,Autophagy ,DNA Methylation ,Chromatin ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Hypomethylating agent ,Cancer cell ,Female ,Lysosomes ,Reprogramming - Abstract
Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression through controlling chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine. In addition to promoting the establishment of an antiviral state, TET2 activated 5mC turnover at thousands of MYC binding motifs and down-regulated a panel of known MYC-repressed genes involved in lysosome biogenesis and function. Thus, an extensive cross-talk between TET2 and the oncogenic transcription factor MYC establishes a lysosomal storage disease-like state that contributes to an exacerbated sensitivity to autophagy inducers.
- Published
- 2021