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

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.

[1]  J. Ortonne,et al.  Sox9 Is Essential for Outer Root Sheath Differentiation and the Formation of the Hair Stem Cell Compartment , 2005, Current Biology.

[2]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[3]  Hongyun Wang,et al.  ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer. , 2013, The Journal of clinical investigation.

[4]  D. Cui,et al.  MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. , 2013, Cancer research.

[5]  Li Zhao,et al.  Oncogenic PI3K deregulates transcription and translation , 2005, Nature Reviews Cancer.

[6]  Takashi Nakamura,et al.  Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways , 2011, Development.

[7]  Y. Suh,et al.  c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells , 2012, Oncogene.

[8]  Hongyun Wang,et al.  SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. , 2008, Cancer research.

[9]  L. Marchionni,et al.  An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. , 2011, Cancer research.

[10]  V. Lefebvre,et al.  Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. , 2007, The international journal of biochemistry & cell biology.

[11]  Julian Downward,et al.  RAS Interaction with PI3K: More Than Just Another Effector Pathway. , 2011, Genes & cancer.

[12]  J. Cuzick,et al.  SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. , 2010, Cancer research.

[13]  J. Marine,et al.  Sox9 Controls Self-Renewal of Oncogene Targeted Cells and Links Tumor Initiation and Invasion. , 2015, Cell stem cell.

[14]  A. Swain,et al.  The role of Sox9 in prostate development. , 2008, Differentiation; research in biological diversity.

[15]  S. Vandenberg,et al.  PDGFRα-Positive B Cells Are Neural Stem Cells in the Adult SVZ that Form Glioma-like Growths in Response to Increased PDGF Signaling , 2006, Neuron.

[16]  Deyou Zheng,et al.  SOX9: a stem cell transcriptional regulator of secreted niche signaling factors , 2014, Genes & development.

[17]  G Parmigiani,et al.  Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer , 2008, Oncogene.

[18]  R. Schwanbeck,et al.  Notch1 signaling regulates chondrogenic lineage determination through Sox9 activation , 2011, Cell Death and Differentiation.

[19]  E. Fuchs,et al.  Hair follicle stem cells are specified and function in early skin morphogenesis. , 2008, Cell stem cell.

[20]  V. Vidal,et al.  SOX9 expression is a general marker of basal cell carcinoma and adnexal‐related neoplasms , 2008, Journal of cutaneous pathology.

[21]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[22]  W. Weiss,et al.  Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines , 2009, Oncogene.

[23]  C. L. Murphy,et al.  Hypoxia Promotes the Differentiated Human Articular Chondrocyte Phenotype through SOX9-dependent and -independent Pathways* , 2008, Journal of Biological Chemistry.

[24]  H. Blum,et al.  Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology , 2013, Molecular Cancer Research.

[25]  Xun Zhang,et al.  Stemness-related markers in cancer , 2017, Cancer translational medicine.

[26]  Mark W. Dewhirst,et al.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response , 2006, Nature.

[27]  B. Hemmings,et al.  Advances in protein kinase B signalling: AKTion on multiple fronts. , 2004, Trends in biochemical sciences.

[28]  K. Jensen,et al.  Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[29]  R. Lovell-Badge,et al.  SOX9 induces and maintains neural stem cells , 2010, Nature Neuroscience.

[30]  Hans Clevers,et al.  SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes , 2004, The Journal of cell biology.

[31]  Mark D. Johnson,et al.  Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for gliomatumorigenesis. , 2016, American journal of translational research.