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Citation
Tags
HERO ID
7383480
Reference Type
Journal Article
Title
Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis
Author(s)
Moro, L; Simoneschi, D; Kurz, E; Arbini, AA; Jang, S; Guaragnella, N; Giannattasio, S; Wang, W; Chen, YA; Pires, G; Dang, A; Hernandez, E; Kapur, P; Mishra, A; Tsirigos, A; Miller, G; Hsieh, JT; Pagano, M
Year
2020
Is Peer Reviewed?
1
Journal
Nature Cell Biology
ISSN:
1465-7392
EISSN:
1476-4679
Volume
22
Issue
9
Page Numbers
1130-1142
Language
English
PMID
32839549
DOI
10.1038/s41556-020-0560-6
Web of Science Id
WOS:000562359000002
Abstract
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.
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