TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1

Guillem Lambies, Martina Miceli, Catalina Martínez-Guillamon, Ruben Olivera-Salguero, Raul Peña, Carolina Paola Frías, Irene Calderon, Boyko S. Atanassov, Sharon Y.R. Dent, Joaquín Arribas, Antonio García de Herreros, Víctor M. Díaz

Research output: Contribution to journalArticleResearchpeer-review

43 Citations (Scopus)

Abstract

© 2018 American Association for Cancer Research. In cancer cells, epithelial-to-mesenchymal transition (EMT) is controlled by Snail1, a transcriptional factor also required for the activation of cancer-associated fibroblasts (CAF). Snail1 is short-lived in normal epithelial cells as a consequence of its coordinated and continuous ubiquitination by several F-box–specific E3 ligases, but its degradation is prevented in cancer cells and in activated fibroblasts. Here, we performed an siRNA screen and identified USP27X as a deubiquitinase that increases Snail1 stability. Expression of USP27X in breast and pancreatic cancer cell lines and tumors positively correlated with Snail1 expression levels. Accordingly, downregulation of USP27X decreased Snail1 protein in several tumor cell lines. USP27X depletion impaired Snail1-dependent cell migration and invasion and metastasis formation and increased cellular sensitivity to cisplatin. USP27X was upregulated by TGFb during EMT and was required for TGFb-induced expression of Snail1 and other mesenchymal markers in epithelial cells and CAF. In agreement with this, depletion of USP27X prevented TGFb-induced EMT and fibroblast activation. Collectively, these results indicate that USP27X is an essential protein controlling Snail1 expression and function and may serve as a target for inhibition of Snail1-dependent tumoral invasion and chemoresistance.
Original languageEnglish
Pages (from-to)33-46
Number of pages14
JournalCancer Research
Volume79
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Animals
  • Breast Neoplasms/genetics
  • Cancer-Associated Fibroblasts
  • Cell Movement
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness
  • Protein Stability
  • RNA, Small Interfering/genetics
  • Snail Family Transcription Factors/chemistry
  • Transforming Growth Factor beta/genetics
  • Tumor Cells, Cultured
  • Ubiquitin-Specific Proteases/antagonists & inhibitors
  • Ubiquitin/metabolism
  • Xenograft Model Antitumor Assays
  • METASTASIS
  • PROTEIN
  • STABILITY
  • SLUG
  • CANCER INVASION
  • TRANSCRIPTION
  • EMT
  • EPITHELIAL-MESENCHYMAL TRANSITION
  • RESISTANCE
  • EXPRESSION

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