Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis
Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA level...
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| Published in: | Nature cell biology Vol. 22; no. 9; pp. 1130 - 1142 |
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| Main Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01-09-2020
Nature Publishing Group |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased
FBXL7
mRNA and protein levels. Low
FBXL7
mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates
FBXL7
as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
Moro et al. show that hypermethylation-induced silencing of the ubiquitin ligase FBXL7 rescues c-SRC from ubiquitin-mediated degradation and enhances epithelial-to-mesenchymal transition and metastasis. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “A. Moro”, 70126 Bari, Italy L.M. designed and performed most experiments, and co-wrote the manuscript. D.S. performed some biochemical experiments and generated the Fbxl7−/− FC1242 cells. E.K., W.W., A.M. and G.M. designed and performed the mice experiments in the pancreatic model systems. E.K. also performed the FACS analyses. A.A.A. and P.K. analyzed and scored IHC and/or H&E staining. D.S., S.J. and A.T. performed the pan-cancer analysis on TCGA data. N.G. and S.G. performed some experiments on FBXL7 promoter methylation in prostate cancer tissues and cell lines. G.P. performed the ZEB1 IHC. Y-A. C., A.D., E.H. and J-T. H. designed and performed the mice experiments in the prostate model system. M.P. directed and coordinated the study, oversaw the results, and co-wrote the manuscript. All authors discussed the results and commented on the manuscript. Contributions |
| ISSN: | 1465-7392 1476-4679 |
| DOI: | 10.1038/s41556-020-0560-6 |