PMID- 32350066
OWN - NLM
STAT- MEDLINE
DCOM- 20201106
LR  - 20210616
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 80
IP  - 12
DP  - 2020 Jun 15
TI  - FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell 
      Lymphoma Cells.
PG  - 2498-2511
LID - 10.1158/0008-5472.CAN-19-2247 [doi]
AB  - 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.
CI  - (c)2020 American Association for Cancer Research.
FAU - Saffie, Rizwan
AU  - Saffie R
AUID- ORCID: 0000-0001-5777-8479
AD  - Department of Cancer Biology and Abramson Family Cancer Research Institute, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania.
FAU - Zhou, Nan
AU  - Zhou N
AUID- ORCID: 0000-0001-9524-4275
AD  - Department of Cancer Biology and Abramson Family Cancer Research Institute, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania.
FAU - Rolland, Delphine
AU  - Rolland D
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Onder, Ozlem
AU  - Onder O
AUID- ORCID: 0000-0003-0850-1216
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Basrur, Venkatesha
AU  - Basrur V
AD  - Department of Pathology and Clinical Laboratories, University of Michigan, Ann 
      Arbor, Michigan.
FAU - Campbell, Sydney
AU  - Campbell S
AD  - Department of Cancer Biology and Abramson Family Cancer Research Institute, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania.
FAU - Wellen, Kathryn E
AU  - Wellen KE
AD  - Department of Cancer Biology and Abramson Family Cancer Research Institute, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania.
FAU - Elenitoba-Johnson, Kojo S J
AU  - Elenitoba-Johnson KSJ
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Capell, Brian C
AU  - Capell BC
AD  - Penn Epigenetics Institute, Department of Cell and Developmental Biology, 
      University of Pennsylvania Perelman School of Medicine, Philadelphia, 
      Pennsylvania.
AD  - Department of Dermatology, University of Pennsylvania Perelman School of 
      Medicine, Philadelphia, Pennsylvania.
FAU - Busino, Luca
AU  - Busino L
AUID- ORCID: 0000-0001-6758-9276
AD  - Department of Cancer Biology and Abramson Family Cancer Research Institute, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania. businol@upenn.edu.
LA  - eng
GR  - K08 AR070289/AR/NIAMS NIH HHS/United States
GR  - R01 CA207513/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200429
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Chromatin)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (F-Box-WD Repeat-Containing Protein 7)
RN  - 0 (FBXW7 protein, human)
RN  - 0 (KMT2D protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Ubiquitin)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Chromatin/metabolism
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - F-Box-WD Repeat-Containing Protein 7/genetics/*metabolism
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Knockout Techniques
MH  - HEK293 Cells
MH  - Humans
MH  - Lymphoma, Large B-Cell, Diffuse/*genetics/pathology
MH  - Mice
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - Oxidative Phosphorylation
MH  - Proteolysis
MH  - RNA, Small Interfering/metabolism
MH  - Signal Transduction/genetics
MH  - Ubiquitin/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC7417195
MID - NIHMS1594798
COIS- The authors declare no competing financial interests.
EDAT- 2020/05/01 06:00
MHDA- 2020/11/11 06:00
PMCR- 2021/06/15
CRDT- 2020/05/01 06:00
PHST- 2019/07/22 00:00 [received]
PHST- 2020/02/25 00:00 [revised]
PHST- 2020/04/21 00:00 [accepted]
PHST- 2020/05/01 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2020/05/01 06:00 [entrez]
PHST- 2021/06/15 00:00 [pmc-release]
AID - 0008-5472.CAN-19-2247 [pii]
AID - 10.1158/0008-5472.CAN-19-2247 [doi]
PST - ppublish
SO  - Cancer Res. 2020 Jun 15;80(12):2498-2511. doi: 10.1158/0008-5472.CAN-19-2247. 
      Epub 2020 Apr 29.