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Published on: January 31, 2018
SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage
Xuehui Hong1, Wenyu Liu2, Ruipeng Song1
1Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Abstract:
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.
Insights
SOX9 protein is degraded following DNA damage via a novel GSK3β/FBW7α pathway, independent of common DNA repair proteins. This SOX9 degradation impacts cancer cell survival and therapy resistance.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- SOX9 is a transcription factor crucial for cell fate and homeostasis.
- Elevated SOX9 expression drives tumor progression by promoting proliferation and epithelial-mesenchymal transition.
Purpose of the Study:
- To elucidate the regulatory mechanism of SOX9 stability under genotoxic stress.
- To investigate the role of SOX9 in cellular response to DNA damage and its implications in cancer.
Main Methods:
- Investigated SOX9 degradation in cancer and normal cells after UV or chemotherapeutic treatment.
- Utilized phosphomimetic mutations and identified key interacting proteins.
- Assessed the impact of SOX9 overexpression on cell survival after genotoxic stress.
Main Results:
- SOX9 undergoes active degradation in response to DNA damage via a p53, ATM, ATR, and DNA-PK independent pathway.
- GSK3β phosphorylates SOX9, promoting its binding to the E3 ligase FBW7α.
- FBW7α targets SOX9 for ubiquitination and proteasomal degradation at specific residues (T236-T240).
- Overexpressing SOX9 enhances cell survival following genotoxic stress.
Conclusions:
- A novel regulatory axis (FBW7-SOX9) controls SOX9 stability during DNA damage response.
- SOX9 plays a unique role in cellular response to DNA damage.
- This FBW7-SOX9 mechanism may contribute to therapy resistance in cancer.
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