title: SOX9 inhibits β-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties.
abstract: The high mobility group box protein SOX9 and the GLI1 transcription factor play protumorigenic roles in pancreatic ductal adenocarcinoma (PDA). In Kras transgenic mice, each of these factors are crucial for the development of PDA precursor lesions. SOX9 transcription is directly regulated by GLI1, but how SOX9 functions downstream of GLI1 is unclear. We observed positive feedback, such that SOX9-deficient PDA cells have severely repressed levels of endogenous GLI1, attributed to loss of GLI1 protein stability. SOX9 associated with the F-box domain of the SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase component, β-TrCP (also known as F-box/WD repeat-containing protein 1A), and suppressed its association with SKP1 and GLI1, a substrate of SCF-β-TrCP. SOX9 also tethered β-TrCP within the nucleus and promoted its degradation. SOX9 bound to β-TrCP through the SOX9 C-terminal PQA/S domain that mediates transcriptional activation. Suppression of β-TrCP in SOX9-deficient PDA cells restored GLI1 levels and promoted SOX9-dependent cancer stem cell properties. These studies identify SOX9-GLI1 positive feedback as a major determinant of GLI1 protein stability and implicate β-TrCP as a latent SOX9-bound tumor suppressor with the potential to degrade oncogenic proteins in tumor cells.
authors: The Department of Biochemistry, West Virginia University, Morgantown, West Virginia 26506 The Mary Babb Randolph Cancer Center, West Virginia University, West Virginia 26506.
authors: Wentao
authors: W
authors: Deng
authors: Program in Cancer Cell Biology, West Virginia University, Morgantown, West Virginia 26506.
authors: Daniel B
authors: DB
authors: Vanderbilt
authors: The Department of Biochemistry, West Virginia University, Morgantown, West Virginia 26506 The Mary Babb Randolph Cancer Center, West Virginia University, West Virginia 26506.
authors: Chen-Chung
authors: CC
authors: Lin
authors: The Mary Babb Randolph Cancer Center, West Virginia University, West Virginia 26506.
authors: Karen H
authors: KH
authors: Martin
authors: The Mary Babb Randolph Cancer Center, West Virginia University, West Virginia 26506.
authors: Kathleen M
authors: KM
authors: Brundage
authors: The Department of Biochemistry, West Virginia University, Morgantown, West Virginia 26506 The Mary Babb Randolph Cancer Center, West Virginia University, West Virginia 26506 Program in Cancer Cell Biology, West Virginia University, Morgantown, West Virginia 26506 mruppert@hsc.wvu.edu.
authors: J Michael
authors: JM
authors: Ruppert
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D023102:Anoikis; D017209:Apoptosis; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D044844:beta-Transducin Repeat-Containing Proteins
keywords: GLI1; Pancreatic ductal adenocarcinoma; SOX9; β-TrCP
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