Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis Journal Article

   


Authors: Duan, S.; Moro, L.; Qu, R.; Simoneschi, D.; Cho, H.; Jiang, S.; Zhao, H.; Chang, Q.; de Stanchina, E.; Arbini, A. A.; Pagano, M.
Article Title: Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
Abstract: FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1FBXO31 promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and -2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer.
Keywords: ubiquitin; phosphatase; f-box proteins; specificity; activation; cell-lines; kinase; cancer; negative-feedback-regulation; fbxo31
Journal Title: Cell Reports
Volume: 37
Issue: 3
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2021-10-19
Start Page: 109870
Language: English
ACCESSION: WOS:000709243200032
DOI: 10.1016/j.celrep.2021.109870
PROVIDER: wos
PMCID: PMC8577224
PUBMED: 34686346
Notes: Article -- Source: Wos
Altmetric
What is Altmetric?
Citation Impact
What is Dimensions Citation Badge?
BMJ Impact Analytics
MSK Authors
  1. Qing Chang
    36 Chang
  2. Elisa De Stanchina
    347 De Stanchina
  3. HuiYong Zhao
    26 Zhao
Related MSK Work