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CD44 regulates epigenetic plasticity by mediating iron endocytosis

View ORCID ProfileSebastian Müller, Fabien Sindikubwabo, Tatiana Cañeque, Anne Lafon, Antoine Versini, Bérangère Lombard, Damarys Loew, Adeline Durand, Céline Vallot, Sylvain Baulande, Nicolas Servant, Raphaël Rodriguez
doi: https://doi.org/10.1101/693424
Sebastian Müller
1Institut Curie, PSL Université, Paris, France
2Chemical Biology of Cancer Laboratory, CNRS UMR 3666, INSERM U1143
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  • ORCID record for Sebastian Müller
Fabien Sindikubwabo
1Institut Curie, PSL Université, Paris, France
2Chemical Biology of Cancer Laboratory, CNRS UMR 3666, INSERM U1143
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Tatiana Cañeque
1Institut Curie, PSL Université, Paris, France
2Chemical Biology of Cancer Laboratory, CNRS UMR 3666, INSERM U1143
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Anne Lafon
1Institut Curie, PSL Université, Paris, France
2Chemical Biology of Cancer Laboratory, CNRS UMR 3666, INSERM U1143
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Antoine Versini
1Institut Curie, PSL Université, Paris, France
2Chemical Biology of Cancer Laboratory, CNRS UMR 3666, INSERM U1143
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Bérangère Lombard
1Institut Curie, PSL Université, Paris, France
3Proteomics Mass Spectrometry Laboratory
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Damarys Loew
1Institut Curie, PSL Université, Paris, France
3Proteomics Mass Spectrometry Laboratory
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Adeline Durand
1Institut Curie, PSL Université, Paris, France
4Translational Research Department, CNRS UMR 3244
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Céline Vallot
1Institut Curie, PSL Université, Paris, France
4Translational Research Department, CNRS UMR 3244
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Sylvain Baulande
1Institut Curie, PSL Université, Paris, France
5Institut Curie Genomics of Excellence Platform
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Nicolas Servant
1Institut Curie, PSL Université, Paris, France
6CBIO-Centre for Computational Biology, INSERM U900, Mines ParisTech
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Raphaël Rodriguez
1Institut Curie, PSL Université, Paris, France
2Chemical Biology of Cancer Laboratory, CNRS UMR 3666, INSERM U1143
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  • For correspondence: raphael.rodriguez@curie.fr
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SUMMARY

CD44 is a transmembrane glycoprotein that is linked to various biological processes reliant on the epigenetic plasticity of cells, including development, inflammation, immune responses, wound healing and cancer progression. While thoroughly studied, functional regulatory roles of this so-called ‘cell surface marker’ remain elusive. Here, we report the discovery that CD44 mediates endocytosis of iron interacting with hyaluronates in tumorigenic cell lines and primary cancer cells. We found that this glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transition, unlike the canonical transferrin-dependent pathway. This transition is further characterized by molecular changes required for iron-catalyzed oxidative demethylation of the repressive histone mark H3K9me2 that governs the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron, demonstrating a positive feedback loop, which is in contrast to the negative regulation of transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This comprehensive study reveals an alternative iron uptake mechanism that prevails in the mesenchymal state of mammalian cells, illuminating a central role of iron as a rate-limiting regulator of epigenetic plasticity.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 09, 2019.
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CD44 regulates epigenetic plasticity by mediating iron endocytosis
Sebastian Müller, Fabien Sindikubwabo, Tatiana Cañeque, Anne Lafon, Antoine Versini, Bérangère Lombard, Damarys Loew, Adeline Durand, Céline Vallot, Sylvain Baulande, Nicolas Servant, Raphaël Rodriguez
bioRxiv 693424; doi: https://doi.org/10.1101/693424
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CD44 regulates epigenetic plasticity by mediating iron endocytosis
Sebastian Müller, Fabien Sindikubwabo, Tatiana Cañeque, Anne Lafon, Antoine Versini, Bérangère Lombard, Damarys Loew, Adeline Durand, Céline Vallot, Sylvain Baulande, Nicolas Servant, Raphaël Rodriguez
bioRxiv 693424; doi: https://doi.org/10.1101/693424

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