内吞作用
表观遗传学
细胞生物学
化学
转铁蛋白受体
CD44细胞
癌细胞
间充质干细胞
生物
细胞
癌症
生物化学
遗传学
基因
作者
Sebastian Müller,Fabien Sindikubwabo,Tatiana Cañeque,Antonin Morillon,Antoine Versini,Bérangère Lombard,Damarys Loew,Ting‐Di Wu,Christophe Ginestier,Emmanuelle Charafe‐Jauffret,Adeline Durand,Céline Vallot,Sylvain Baulande,Nicolas Servant,Raphaël Rodriguez
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2020-08-03
卷期号:12 (10): 929-938
被引量:158
标识
DOI:10.1038/s41557-020-0513-5
摘要
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.
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