Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer

// Fatima Valdes-Mora 1, 2 , Warwick J. Locke 3 , Eva Bandres 4 , David Gallego-Ortega 2, 5 , Paloma Cejas 6 , Miguel Angel Garcia-Cabezas 7 , Yolanda Colino-Sanguino 1, 2 , Jaime Feliu 6, 8 , Teresa Gomez del Pulgar 6, * , Juan Carlos Lacal 6, * 1 Histone Variants Group, Epigenetics Research Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia 2 St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, New South Wales, Australia 3 Epigenetics Research Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia 4 Immunology Unit, Department of Haematology, Complejo Hospitalario de Navarra, Navarra Health Service, Pamplona, Spain 5 Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia 6 Laboratorio de Oncologia Translacional, Servicio de Oncologia Medica, IdiPAZ, Madrid, Spain 7 Servicio de Anatomia Patologica, Hospital Universitario La Paz, Madrid, Spain 8 Servicio de Oncologia Medica, IdiPAZ, CIBERONC, Madrid, Spain * Co-senior authors Correspondence to: Juan Carlos Lacal, email: jclacal10@gmail.com Fatima Valdes-Mora, email: f.valdesmora@garvan.org.au Keywords: colorectal cancer, CACNA2D2, CDC42, tumor suppressor genes, prognostic factor Received: June 16, 2016      Accepted: February 20, 2017      Published: March 01, 2017 ABSTRACT CDC42 is an oncogenic Rho GTPase overexpressed in colorectal cancer (CRC). Although CDC42 has been shown to regulate gene transcription, the specific molecular mechanisms regulating the oncogenic ability of CDC42 remain unknown. Here, we have characterized the transcriptional networks governed by CDC42 in the CRC SW620 cell line using gene expression analysis. Our results establish that several cancer-related signaling pathways, including cell migration and cell proliferation, are regulated by CDC42. This transcriptional signature was validated in two large cohorts of CRC patients and its clinical relevance was also studied. We demonstrate that three CDC42-regulated genes offered a better prognostic value when combined with CDC42 compared to CDC42 alone. In particular, the concordant overexpression of CDC42 and silencing of the putative tumor suppressor gene CACNA2D2 dramatically improved the prognostic value. The CACNA2D2/CDC42 prognostic classifier was further validated in a third CRC cohort as well as in vitro and in vivo CRC models. Altogether, we show that CDC42 has an active oncogenic role in CRC via the transcriptional regulation of multiple cancer-related pathways and that CDC42-mediated silencing of CACNA2D2 is clinically relevant. Our results further support the use of CDC42 specific inhibitors for the treatment of the most aggressive types of CRC.