SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage

Nucleic Acids Res. 2016 Oct 14;44(18):8855-8869. doi: 10.1093/nar/gkw748. Epub 2016 Aug 26.


SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis and progression of human tumors by increasing cell proliferation and epithelial-mesenchymal transition. We found that in response to UV irradiation or genotoxic chemotherapeutics, SOX9 is actively degraded in various cancer types and in normal epithelial cells, through a pathway independent of p53, ATM, ATR and DNA-PK. SOX9 is phosphorylated by GSK3β, facilitating the binding of SOX9 to the F-box protein FBW7α, an E3 ligase that functions in the DNA damage response pathway. The binding of FBW7α to the SOX9 K2 domain at T236-T240 targets SOX9 for subsequent ubiquitination and proteasomal destruction. Exogenous overexpression of SOX9 after genotoxic stress increases cell survival. Our findings reveal a novel regulatory mechanism for SOX9 stability and uncover a unique function of SOX9 in the cellular response to DNA damage. This new mechanism underlying a FBW7-SOX9 axis in cancer could have implications in therapy resistance.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Cycle Proteins / metabolism*
  • Cell Death
  • Cell Line, Tumor
  • DNA Damage* / drug effects
  • DNA Damage* / radiation effects
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Models, Biological
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proteolysis
  • SOX9 Transcription Factor / chemistry
  • SOX9 Transcription Factor / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Ultraviolet Rays / adverse effects


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • SOX9 Transcription Factor
  • Ubiquitin-Protein Ligases
  • Glycogen Synthase Kinase 3 beta
  • Proteasome Endopeptidase Complex