Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells

// Sarmistha Talukdar 1,2 , Swadesh K. Das 1,2,3 , Anjan K. Pradhan 1,2 , Luni Emdad 1,2,3 , Xue-Ning Shen 1,2 , Jolene J. Windle 1,2,3 , Devanand Sarkar 1,2,3 and Paul B. Fisher 1,2,3 1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA 2 VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA 3 VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA Correspondence to: Paul B. Fisher, email: // Keywords : MDA-9/Syntenin (SDCBP); stemness; glioma stem cells; survival; apoptosis Received : May 31, 2016 Accepted : July 07, 2016 Published : July 26, 2016 Abstract Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs. Consequently, there is a pressing need to identify therapeutic targets and novel options to effectively target this therapy-resistant cell population. The precise roles of GSCs in governing GBM development, progression and prognosis are under intense scrutiny, but key upstream regulatory genes remain speculative. MDA-9/Syntenin (SDCBP), a scaffold protein, regulates tumor pathogenesis in multiple cancers. Highly aggressive cancers like GBM express elevated levels of MDA-9 and contain increased populations of GSCs. We now uncover a unique function of MDA-9 as a facilitator and determinant of glioma stemness and survival. Mechanistically, MDA-9 regulates multiple stemness genes ( Nanog, Oct4 and Sox2 ) through activation of STAT3. MDA-9 controls survival of GSCs by activating the NOTCH1 pathway through phospho-Src and DLL1. Once activated, cleaved NOTCH1 regulates C-Myc expression through RBPJK, thereby facilitating GSC growth and proliferation. Knockdown of MDA-9 affects the NOTCH1/C-Myc and p-STAT3/Nanog pathways causing a loss of stemness and initiation of apoptosis in GSCs. Our data uncover a previously unidentified relationship between MDA-9 and GSCs, reinforcing relevance of this gene as a potential therapeutic target in GBM.