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

被引：24

作者：

Duan, Shanshan ^{[1
,2
]}

Moro, Loredana ^{[1
,2
]}

Qu, Rui ^{[1
,2
]}

Simoneschi, Daniele ^{[1
,2
]}

Cho, Hyunwoo ^{[1
,2
]}

Jiang, Shaowen ^{[1
,2
]}

Zhao, Huiyong ^{[3
]}

Chang, Qing ^{[3
]}

de Stanchina, Elisa ^{[3
]}

Arbini, Arnaldo A. ^{[2
,4
]}

Pagano, Michele ^{[1
,2
,5
]}

机构：

[1] NYU, Alexandria Ctr Life Sci, Dept Biochem & Mol Pharmacol, Grossman Sch Med, New York, NY 10016 USA

[2] NYU, Alexandria Ctr Life Sci, Laura & Isaac Perlmutter Canc Ctr, Grossman Sch Med, New York, NY 10016 USA

[3] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA

[4] NYU, Alexandria Ctr Life Sci, Dept Pathol, Grossman Sch Med, 550 1St Ave, New York, NY 10016 USA

[5] NYU, Alexandria Ctr Life Sci, Howard Hughes Med Inst, Grossman Sch Med, New York, NY 10016 USA

来源：

CELL REPORTS | 2021年 / 37卷 / 03期

关键词：

NEGATIVE-FEEDBACK-REGULATION; F-BOX PROTEINS; CELL-LINES; CANCER; SPECIFICITY; KINASE; PHOSPHATASE; ACTIVATION; UBIQUITIN; FBXO31;

D O I：

10.1016/j.celrep.2021.109870

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：16

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