Journal
CELL REPORTS
Volume 30, Issue 13, Pages 4551-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.03.022
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Funding
- European Union [259735]
- Plan Cancer, Epigenetique et Cancer [EPIG201303 METABEPIC]
- Paradifference Foundation
- Cancer Research for Personalized Medicine (CARPEM) project (Site de Recherche Integre sur le Cancer [SIRIC])
- Cartes d'Identite des Tumeurs (CIT) program
- La Fondation pour la Recherche Medicale
- La Ligue Nationale contre le Cancer
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Loss-of-function mutations in the SDHB subunit of succinate dehydrogenase predispose patients to aggressive tumors characterized by pseudohypoxic and hypermethylator phenotypes. The mechanisms leading to DNA hypermethylation and its contribution to SDH-deficient cancers remain un-demonstrated. We examine the genome-wide distribution of 5-methylcytosine and 5-hydroxymethylcytosine and their correlation with RNA expression in SDHB-deficient tumors and murine Sdhb(-/-) cells. We report that DNA hypermethylation results from TET inhibition. Although it preferentially affects PRC2 targets and known developmental genes, PRC2 activity does not contribute to the DNA hypermethylator phenotype. We also prove, in vitro and in vivo, that TET silencing, although recapitulating the methylation profile of Sdhb(-/-) cells, is not sufficient to drive their EMT-like phenotype, which requires additional HIF2 alpha activation. Altogether, our findings reveal synergistic roles of TET repression and pseudohypoxia in the acquisition of metastatic traits, providing a rationale for targeting HIF2a and DNA methylation in SDH-associated malignancies.
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