Fiche publication
Date publication
juin 2020
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROLLAND Delphine
Tous les auteurs :
Saffie R, Zhou N, Rolland D, Önder Ö, Basrur V, Campbell S, Wellen KE, Elenitoba-Johnson KSJ, Capell BC, Busino L
Lien Pubmed
Résumé
Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. SIGNIFICANCE: These findings characterize FBXW7 as a prosurvival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D.
Mots clés
Animals, Cell Line, Tumor, Cell Proliferation, genetics, Chromatin, metabolism, DNA-Binding Proteins, genetics, F-Box-WD Repeat-Containing Protein 7, genetics, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, HEK293 Cells, Humans, Lymphoma, Large B-Cell, Diffuse, genetics, Mice, Neoplasm Proteins, genetics, Oxidative Phosphorylation, Proteolysis, RNA, Small Interfering, metabolism, Signal Transduction, genetics, Ubiquitin, metabolism, Xenograft Model Antitumor Assays
Référence
Cancer Res. 2020 06 15;80(12):2498-2511
