Dataset Information

CD44 regulates epigenetic plasticity by mediating iron endocytosis - part 1

ABSTRACT: The biological process termed Epithelial-to-Mesenchymal Transition (EMT) plays a central role in cancer cell invasion, metastasis, self-renewal and resistance to therapy. Here, we characterize using quantitative LC-MS/MS the global changes in proteins levels occurring during EMT induced by epidermal growth factor in breast cancer MDA-MB-468 cells.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Mammary Gland

SUBMITTER: Guillaume Arras

LAB HEAD: Damarys Loew

PROVIDER: PXD011447 | Pride | 2019-10-01

REPOSITORIES: Pride

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CD44 regulates epigenetic plasticity by mediating iron endocytosis.

Müller Sebastian S Sindikubwabo Fabien F Cañeque Tatiana T Lafon Anne A Versini Antoine A Lombard Bérangère B Loew Damarys D Wu Ting-Di TD Ginestier Christophe C Charafe-Jauffret Emmanuelle E Durand Adeline A Vallot Céline C Baulande Sylvain S Servant Nicolas N Rodriguez Raphaël R

Nature chemistry 20200803 10

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 ...[more]

PMID: 32747755

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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

Dataset Information

CD44 regulates epigenetic plasticity by mediating iron endocytosis - part 1

Publications

CD44 regulates epigenetic plasticity by mediating iron endocytosis.

Similar Datasets

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