SOX9 is Targeted for Proteasomal Degradation by the E3 Ligase FBW7 in Response to DNA Damage

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2016 Aug 28

PMID 27566146

Citations 30

Authors

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

Affiliations

Soon will be listed here.

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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