FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.
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
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 06 2020
15 06 2020
Historique:
received:
22
07
2019
revised:
25
02
2020
accepted:
21
04
2020
pubmed:
1
5
2020
medline:
11
11
2020
entrez:
1
5
2020
Statut:
ppublish
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.
Identifiants
pubmed: 32350066
pii: 0008-5472.CAN-19-2247
doi: 10.1158/0008-5472.CAN-19-2247
pmc: PMC7417195
mid: NIHMS1594798
doi:
Substances chimiques
Chromatin
0
DNA-Binding Proteins
0
F-Box-WD Repeat-Containing Protein 7
0
FBXW7 protein, human
0
KMT2D protein, human
0
Neoplasm Proteins
0
RNA, Small Interfering
0
Ubiquitin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2498-2511Subventions
Organisme : NIAMS NIH HHS
ID : K08 AR070289
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207513
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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