CD44 regulates epigenetic plasticity by mediating iron endocytosis
- 2 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemistry
- Vol. 12 (10), 929-+
- https://doi.org/10.1038/s41557-020-0513-5
Abstract
CD44 is a transmembrane glycoprotein linked to various biological processes reliant on epigenetic plasticity, which include development, inflammation, immune responses, wound healing and cancer progression. Although it is often referred to as a cell surface marker, the functional regulatory roles of CD44 remain elusive. Here we report the discovery that CD44 mediates the endocytosis of iron-bound hyaluronates in tumorigenic cell lines, primary cancer cells and tumours. This glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transitions, in which iron operates as a metal catalyst to demethylate repressive histone marks that govern the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron through a positive feedback loop, which is in contrast to the negative regulation of the transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This study reveals an alternative iron-uptake mechanism that prevails in the mesenchymal state of cells, which illuminates a central role of iron as a rate-limiting regulator of epigenetic plasticity.This publication has 51 references indexed in Scilit:
- High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole ratNature, 2013
- N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTONature Chemical Biology, 2011
- Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transitionNature Structural & Molecular Biology, 2011
- PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progressionNature, 2010
- Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial developmentNature, 2010
- Iron control of erythroid development by a novel aconitase-associated regulatory pathwayBlood, 2010
- PHF8 Targets Histone Methylation and RNA Polymerase II To Activate TranscriptionMolecular and Cellular Biology, 2010
- Complex Display of Putative Tumor Stem Cell Markers in the NCI60 Tumor Cell Line PanelThe International Journal of Cell Cloning, 2010
- Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal TransitionPLOS ONE, 2008
- The Obesity-AssociatedFTOGene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid DemethylaseScience, 2007