PT - JOURNAL ARTICLE AU - Audrey Laurent AU - Thierry Madigou AU - Maud Bizot AU - Marion Turpin AU - Gaëlle Palierne AU - Elise Mahé AU - Sarah Guimard AU - Raphaël Métivier AU - Stéphane Avner AU - Christine Le Péron AU - Gilles Salbert TI - TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis AID - 10.26508/lsa.202101283 DP - 2022 Jul 01 TA - Life Science Alliance PG - e202101283 VI - 5 IP - 7 4099 - https://www.life-science-alliance.org/content/5/7/e202101283.short 4100 - https://www.life-science-alliance.org/content/5/7/e202101283.full SO - Life Sci. Alliance2022 Jul 01; 5 AB - Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression by controlling the 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. The 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.