SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

// Corinne Prévostel 1, 2, 3, 4 , Cyrine Rammah-Bouazza 5 , Hélène Trauchessec 5 , Lucile Canterel-Thouennon 1, 2, 3, 4 , Muriel Busson 1, 2, 3, 4 , Marc Ychou 1, 2, 3, 4, 6, 7 , Philippe Blache 1, 2, 3, 4 1 IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France 2 INSERM, U1194, Montpellier, France 3 Université de Montpellier, Montpellier, France 4 Institut régional du Cancer de Montpellier, Montpellier, France 5 Université de Montpellier, UMR 5237, Centre de Recherche de Biochimie Macromoléculaire, CNRS, Montpellier, France 6 Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France 7 Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France Correspondence to: Corinne Prévostel, email: corinne.prevostel@inserm.fr Philippe Blache, email: philippe.blache@inserm.fr Keywords: SOX9, colorectal cancer, tumor suppressor, Wnt/ß-catenin inhibition, c-myc inhibition Received: December 09, 2015 Accepted: June 26, 2016 Published: July 13, 2016 ABSTRACT SOX9 inactivation is frequent in colorectal cancer (CRC) due to SOX9 gene mutations and/or to ectopic expression of MiniSOX9, a dominant negative inhibitor of SOX9. In the present study, we report a heterozygous L142P inactivating mutation of SOX9 in the DLD-1 CRC cell line and we demonstrate that the conditional expression of a wild type SOX9 in this cell line inhibits cell growth, clonal capacity and colonosphere formation while decreasing both the activity of the oncogenic Wnt/ß-catenin signaling pathway and the expression of the c-myc oncogene. This activity does not require SOX9 transcriptional function but, rather, involves an interaction of SOX9 with nuclear ß-catenin. Furthermore, we report that SOX9 inhibits tumor development when conditionally expressed in CRC cells injected either subcutaneous or intraperitoneous in BALB/c mice as an abdominal metastasis model. These observations argue in favor of a tumor suppressor activity for SOX9. As an siRNA targeting SOX9 paradoxically also inhibits DLD-1 and HCT116 CRC cell growth, we conclude that there is a critical level of endogenous active SOX9 needed to maintain CRC cell growth.