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Cancer Cell. 2016 Feb 8;29(2):201-13. doi: 10.1016/j.ccell.2016.01.005.

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

Author information

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: inakano@uabmc.edu.

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

PMID:
26859459
PMCID:
PMC4837946
DOI:
10.1016/j.ccell.2016.01.005
[Indexed for MEDLINE]
Free PMC Article

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