CD44 regulates epigenetic plasticity by mediating iron endocytosis

Abstract

CD44 is a transmembrane glycoprotein that is linked to various biological processes reliant on the epigenetic plasticity of cells, including development, inflammation, immune responses, 20wound 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 30 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.

Salinomycin Derivatives Kill Breast Cancer Stem Cells by Lysosomal Iron Targeting

“…[16] In order to limit the productiono fu ndesired side products, as yringep ump was used to ensure the slow addition of reducing agent. In light of the good conversion of the starting material, this protocol was employedfor the synthesis of asmall C20-functionalized library.T his allowed us to introduce al arge diversity of functional groups at this position, includingc ycloalkyl (4-8), pyridines (9-10), phenols (11-13), fluoro aromatics (14)(15)(16), or aliphatic chains (19)(20)(21)w ith yields ranging between 7% and 39 %. In all cases, we could observe the formation of various amountso fb yproducts resulting from the reduction of C18-C19 of the desired amine products.…”

“…In comparison, our data indicate that it is unlikely that the breast CSC activity of Sal is linked to sodium transport. Regardless, the ability of Sal and derivatives to sequester iron in lysosomes, to induce the production of ROS selectively in this organelle, and to elicit lethal lysosome membrane permeabilization argues in favor of iron being a druggable target in breast CSC . This is consistent with the well‐established addiction of CSC to iron and their vulnerability to ferroptosis .…”

“…Our prior work led to the discovery that CSC upregulate cellular iron homeostasis and contain a higher load of iron, a finding that was corroborated by other studies, illustrating the value of developing compounds susceptible to interfere with iron metabolism in CSC . In line with this, more recent work revealed an unprecedented iron endocytosis pathway that prevails in the mesenchymal state of cells and showed that iron is a master regulator of epigenetic plasticity, acting as a metal catalyst to regulate the methylation status of histone residues involved in the regulation of EMT . Mechanistically, we showed that Sal and Ironomycin ( 2 ) exert their activity by accumulating in and sequestering iron in lysosomes, thereby interfering with iron‐dependent processes.…”

Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death

“…In 2011, the transmembrane glycoprotein CD44, a cancer stem-like cell marker, and more precisely the CD44 variant (CD44 v ) capable to bind hyaluronan has also been described to interacts and stabilizes X − c system (14) (Figure 1). Although the role of CD44 in the transport activity of xCT has not been validated so far, an interesting implication in iron endocytosis via CD44-bound hyaluronates is proposed (15) (Figure 1). Our group recently described that a genetic disruption of the xCT subunit using CRISPR-Cas9 inhibits protein synthesis and proliferation in vitro (16) and leads to a specific non-apoptotic cell death named ferroptosis, that will be described later in this review.…”

From Iron Chelation to Overload as a Therapeutic Strategy to Induce Ferroptosis in Leukemic Cells

“…Furthermore, autophagy-mediated ferritin degradation and iron subsequent supply play a key role in ferroptosis, explaining at least in part the anti-tumor activity of dihydroartemisin via the activation of the AMPK-mTOR signaling pathway ( 92 ). Recently, iron has shown the capacity to catalyze the oxidative demethylation of protein residues and nucleobases in association as a cofactor of demethylases like PHF8, which is a great interest in AML since demethylating agents have proven efficacy in this context ( 107 ). A putative model of the iron metabolism modulation that triggers ferroptosis is provided in Figure 2 .…”