Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis

Loredana Moro, Daniele Simoneschi, Emma Kurz, Arnaldo A. Arbini, Shaowen Jang, Nicoletta Guaragnella, Sergio Giannattasio, Wei Wang, Yu An Chen, Geoffrey Pires, Andrew Dang, Elizabeth Hernandez, Payal Kapur, Ankita Mishra, Aristotelis Tsirigos, George Miller, Jer Tsong Hsieh, Michele Pagano

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1130-1142
Number of pages13
JournalNature cell biology
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Cell Biology

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    Moro, L., Simoneschi, D., Kurz, E., Arbini, A. A., Jang, S., Guaragnella, N., Giannattasio, S., Wang, W., Chen, Y. A., Pires, G., Dang, A., Hernandez, E., Kapur, P., Mishra, A., Tsirigos, A., Miller, G., Hsieh, J. T., & Pagano, M. (2020). Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis. Nature cell biology, 22(9), 1130-1142. https://doi.org/10.1038/s41556-020-0560-6