SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation

• Type of Material: Article
• Authors: Birdal Bilir, Emory University; Adeboye Osunkoya, Emory University; W Guy Wiles, Emory University; Soma Sannigrahi, Emory University; Veronique Lefebvre, Cleveland Clinic; Daniel Metzger, University of Strasbourg; Demetri D Spyropoulos, Medical University of South Carolina; W. Martin, Emory University; Carlos Moreno, Emory University
• Language: English
• Date: 2016-03-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-15-1868
• Title of Journal or Parent Work: Cancer Research
• Volume: 76
• Issue: 5
• Start Page: 1112
• End Page: 1121
• Grant/Funding Information: The Amy & Nevin Kreisler Research Award, a philanthropic award provided by the Winship Cancer Institute of Emory University.; Cancer Animal Models Systems Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292; NIH grant R01CA106826 and NIH U01 CA168449; DM was supported by the Centre National pour la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Fondation ARC pour la Recherche sur le Cancer and the Ligue Nationale Contre le Cancer, and by French state funds through the Agence Nationale de la Recherche ANR-10-LABX-0030-INRT under the frame programme Investissements d’Avenir labelled ANR-10-IDEX-0002-02
• Keywords: WNT; BETA-CATENIN; TUMOR-SUPPRESSOR; GROWTH; Oncology; SIGNALING PATHWAY; Life Sciences & Biomedicine; METASTASIS; Science & Technology; CANCER CELLS; CARCINOMA; TRANSCRIPTION FACTORS; PROGRESSION
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

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.