Oncotarget

Priority Research Papers:

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

Sarmistha Talukdar, Swadesh K. Das, Anjan K. Pradhan, Luni Emdad, Xue-Ning Shen, Jolene J. Windle, Devanand Sarkar, Paul B. Fisher _

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Abstract

Sarmistha Talukdar1,2, Swadesh K. Das1,2,3, Anjan K. Pradhan1,2, Luni Emdad1,2,3, Xue-Ning Shen1,2, Jolene J. Windle1,2,3, Devanand Sarkar1,2,3 and Paul B. Fisher1,2,3

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.

Author Information

Sarmistha Talukdar

Swadesh K. Das

Anjan K. Pradhan

Luni Emdad

Xue-Ning Shen

Jolene J. Windle

Devanand Sarkar

Paul B. Fisher
Primary Contact  _


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