title: SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation.
abstract: Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K-AKT-mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K-AKT-mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors.forename: Birdal
authors.initials: B
authors.lastname: Bilir
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Department of Urology, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Adeboye O
authors.initials: AO
authors.lastname: Osunkoya
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: W Guy
authors.initials: WG
authors.lastname: Wiles
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Hubert Department of Global Health Infectious Diseases, Rollins School of Public Health, Emory University, Atlanta, Georgia.
authors.forename: Soma
authors.initials: S
authors.lastname: Sannigrahi
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Veronique
authors.initials: V
authors.lastname: Lefebvre
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104/Université de Strasbourg, Illkirch, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Demetri D
authors.initials: DD
authors.lastname: Spyropoulos
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: W David
authors.initials: WD
authors.lastname: Martin
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia. cmoreno@emory.edu.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011471:Prostatic Neoplasms / Q000209:etiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology; D055751:SOXC Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D055751:SOXC Transcription Factors; D058570:TOR Serine-Threonine Kinases; D051176:beta Catenin; C083431:SOX4 protein, human; C494929:PTEN protein, human