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

Nucleic acids research (2016-08-28)
Xuehui Hong, Wenyu Liu, Ruipeng Song, Jamie J Shah, Xing Feng, Chi Kwan Tsang, Katherine M Morgan, Samuel F Bunting, Hiroyuki Inuzuka, X F Steven Zheng, Zhiyuan Shen, Hatem E Sabaawy, LianXin Liu, Sharon R Pine
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.

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