SOX9-PDK1 axis is essential for glioma stem cell self-renewal and temozolomide resistance

Abstract

// Zhen Wang 1, 5, * , Xiaoshan Xu 1, * , Nan Liu 1, * , Yingduan Cheng 1, 2 , Weilin Jin 3 , Pengxing Zhang 1 , Xin Wang 4 , Hongwei Yang 4 , Hui Liu 1 and Yanyang Tu 1, 4, * 1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical, University, Xi’an 710038, China 2 Department of Research, Cipher Ground, North Brunswick, NJ 08902, USA 3 Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China 4 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA 5 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiao Tong University, Xi’an 710049, China * These authors contributed equally to this work Correspondence to: Yanyang Tu, email: ayonst@163.com Keywords: glioblastoma multiforme; SOX9; PDK1; self-renewal; temozolomide Received: June 05, 2017      Accepted: November 15, 2017      Published: November 30, 2017 ABSTRACT Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with limited therapeutic options. Glioma stem cell (GSC) is thought to be greatly responsible for glioma tumor progression and drug resistance. But the molecular mechanisms of GSC deriving recurrence and drug resistance are still unclear. SOX9 (sex-determining region Y (SRY)-box9 protein), a transcription factor expressed in most solid tumors, is reported as a key regulator involved in maintaining cancer hallmarks including the GSCs state. Previously, we have observed that silencing of SOX9 suppressed glioma cells proliferation both in vitro and in vivo . Here, we found that SOX9 was essential for GSC self-renewal. Silencing of SOX9 down-regulated a broad range of stem cell markers and inhibited glioma cell colony and sphere formation. We identified pyruvate dehydrogenase kinase 1 ( PDK1 ) as a target gene of SOX9 using microarray analyses. PDK1 inactivation greatly inhibited glioma cell colony and sphere formation and sensitized glioma spheres to temozolomide (TMZ) toxicity. In addition, SOX9-shRNA and PDK1 inhibitor could greatly sensitize GSC to TMZ in vivo . Taken together, our data reveals that SOX9-PDK1 axis is a key regulator of GSC self-renewal and GSC temozolomide resistance. These findings may provide help for future human GBM therapy.