Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner

  • Cancer Cell. 2016 Feb 8;29(2):201-13. doi: 10.1016/j.ccell.2016.01.005.
Sung-Hak Kim  1 ,  Ravesanker Ezhilarasan  2 ,  Emma Phillips  3 ,  Daniel Gallego-Perez  4 ,  Amanda Sparks  5 ,  David Taylor  5 ,  Katherine Ladner  6 ,  Takuya Furuta  7 ,  Hemragul Sabit  7 ,  Rishi Chhipa  8 ,  Ju Hwan Cho  9 ,  Ahmed Mohyeldin  5 ,  Samuel Beck  10 ,  Kazuhiko Kurozumi  11 ,  Toshihiko Kuroiwa  12 ,  Ryoichi Iwata  13 ,  Akio Asai  13 ,  Jonghwan Kim  10 ,  Erik P Sulman  2 ,  Shi-Yuan Cheng  14 ,  L James Lee  15 ,  Mitsutoshi Nakada  7 ,  Denis Guttridge  6 ,  Biplab DasGupta  8 ,  Violaine Goidts  3 ,  Krishna P Bhat  16 ,  Ichiro Nakano  17
Affiliations
  • 1. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 2. Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 3. Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
  • 4. Department of Surgery, The Ohio State University, Columbus, OH 43210, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA; Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH 43210, USA; Center for Regenerative Medicine and Cell-Based Therapies, The Ohio State University, Columbus, OH 43210, USA.
  • 5. Department of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
  • 6. Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
  • 7. Department of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
  • 8. Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242, USA.
  • 9. Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
  • 10. Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, TX 78712, USA.
  • 11. Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
  • 12. Department of Neurosurgery, Osaka Medical College, Osaka 569-8686, Japan.
  • 13. Department of Neurosurgery, Kansai Medical University, Osaka 573-1191, Japan.
  • 14. The Ken & Ruth Davee Department of Neurology & Northwestern Brain Tumor Institute, Center for Genetic Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 15. Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH 43210, USA; Center for Regenerative Medicine and Cell-Based Therapies, The Ohio State University, Columbus, OH 43210, USA; Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA.
  • 16. Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 17. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: [email protected].
PMID: 26859459 DOI: 10.1016/j.ccell.2016.01.005
Abstract

Activation of nuclear factor κB (NF-κB) induces mesenchymal (MES) transdifferentiation and radioresistance in Glioma stem cells (GSCs), but molecular mechanisms for NF-κB activation in GSCs are currently unknown. Here, we report that Mixed Lineage Kinase 4 (MLK4) is overexpressed in MES but not proneural (PN) GSCs. Silencing MLK4 suppresses self-renewal, motility, tumorigenesis, and radioresistance of MES GSCs via a loss of the MES signature. MLK4 binds and phosphorylates the NF-κB regulator IKKα, leading to activation of NF-κB signaling in GSCs. MLK4 expression is inversely correlated with patient prognosis in MES, but not PN high-grade gliomas. Collectively, our results uncover MLK4 as an upstream regulator of NF-κB signaling and a potential molecular target for the MES subtype of glioblastomas.

Keywords
cancer stem cell; epithelial-to-mesenchymal transition; glioblastoma; proneural-mesenchymal transition.