FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.

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.
Mesh Terms:
Animals, Cell Line, Tumor, Cell Proliferation, Chromatin, DNA-Binding Proteins, F-Box-WD Repeat-Containing Protein 7, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, HEK293 Cells, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Neoplasm Proteins, Oxidative Phosphorylation, Proteolysis, RNA, Small Interfering, Signal Transduction, Ubiquitin, Xenograft Model Antitumor Assays
Cancer Res
Date: Dec. 15, 2019
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