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

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, Lian Xin Liu, Sharon R. Pine

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8855-8869
Number of pages15
JournalNucleic acids research
Volume44
Issue number18
DOIs
Publication statusPublished - 2016 Oct 14

ASJC Scopus subject areas

  • Genetics

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    Hong, X., Liu, W., Song, R., Shah, J. J., Feng, X., Tsang, C. K., Morgan, K. M., Bunting, S. F., Inuzuka, H., Zheng, X. F. S., Shen, Z., Sabaawy, H. E., Liu, L. X., & Pine, S. R. (2016). SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage. Nucleic acids research, 44(18), 8855-8869. https://doi.org/10.1093/nar/gkw748