title: SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.
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.
authors: Rutgers 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.
authors: Xuehui
authors: X
authors: Hong
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Wenyu
authors: W
authors: Liu
authors: Rutgers 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.
authors: Ruipeng
authors: R
authors: Song
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Jamie J
authors: JJ
authors: Shah
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
authors: Xing
authors: X
authors: Feng
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors: Chi Kwan
authors: CK
authors: Tsang
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Katherine M
authors: KM
authors: Morgan
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Biochemistry and Molecular Biology, Rutgers Graduate School of Biomedical Sciences, Piscataway, NJ 08854, USA.
authors: Samuel F
authors: SF
authors: Bunting
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Hiroyuki
authors: H
authors: Inuzuka
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors: X F Steven
authors: XF
authors: Zheng
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
authors: Zhiyuan
authors: Z
authors: Shen
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903-0019, USA.
authors: Hatem E
authors: HE
authors: Sabaawy
authors: Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China liulianxin@ems.hrbmu.edu.cn.
authors: LianXin
authors: L
authors: Liu
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903-0019, USA pinesr@cinj.rutgers.edu.
authors: Sharon R
authors: SR
authors: Pine
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D055758:SOX9 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D055758:SOX9 Transcription Factor; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; D046988:Proteasome Endopeptidase Complex