Transforming growth factor-β suppresses the ability of ski to inhibit tumor metastasis by inducing its degradation

Erwan Le Scolan, Qingwei Zhu, Long Wang, Abhik Bandyopadhyay, Delphine Javelaud, Alain Mauviel, Luzhe Sun, Kunxin Luo

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

c-Ski is an important corepressor of transforming growth factor-β (TGF-β) signaling through its ability to bind to and repress the activity of the Smad proteins. It was initially identified as an oncogene that promotes anchorage-independent growth of chicken and quail embryo fibroblasts when overexpressed. Although increased Ski expression is detected in many human cancer cells, the roles of Ski in mammalian carcinogenesis have yet to be defined. Here, we report that reducing Ski expression in breast and lung cancer cells does not affect tumor growth but enhances tumor metastasis in vivo. Thus, in these cells, Ski plays an antitumorigenic role. We also showed that TGF-β, a cytokine that is often highly expressed in metastatic tumors, induces Ski degradation through the ubiquitin-dependent proteasome in malignant human cancer cells. On TGF-β treatment, the E3 ubiquitin ligase Arkadia mediates degradation of Ski in a Smad-dependent manner. Although Arkadia interacts with Ski in the absence of TGF-β, binding of phosphorylated Smad2 or Smad3 to Ski is required to induce efficient degradation of Ski by Arkadia. Our results suggest that the ability of TGF-β to induce degradation of Ski could be an additional mechanism contributing to its protumorigenic activity.

Original languageEnglish (US)
Pages (from-to)3277-3285
Number of pages9
JournalCancer Research
Volume68
Issue number9
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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