title: Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner.
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.
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Sung-Hak
authors: SH
authors: Kim
authors: Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Ravesanker
authors: R
authors: Ezhilarasan
authors: Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors: Emma
authors: E
authors: Phillips
authors: 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.
authors: Daniel
authors: D
authors: Gallego-Perez
authors: Department of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Amanda
authors: A
authors: Sparks
authors: Department of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors: David
authors: D
authors: Taylor
authors: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors: Katherine
authors: K
authors: Ladner
authors: Department of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
authors: Takuya
authors: T
authors: Furuta
authors: Department of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
authors: Hemragul
authors: H
authors: Sabit
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242, USA.
authors: Rishi
authors: R
authors: Chhipa
authors: Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Ju Hwan
authors: JH
authors: Cho
authors: Department of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Ahmed
authors: A
authors: Mohyeldin
authors: 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.
authors: Samuel
authors: S
authors: Beck
authors: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors: Kazuhiko
authors: K
authors: Kurozumi
authors: Department of Neurosurgery, Osaka Medical College, Osaka 569-8686, Japan.
authors: Toshihiko
authors: T
authors: Kuroiwa
authors: Department of Neurosurgery, Kansai Medical University, Osaka 573-1191, Japan.
authors: Ryoichi
authors: R
authors: Iwata
authors: Department of Neurosurgery, Kansai Medical University, Osaka 573-1191, Japan.
authors: Akio
authors: A
authors: Asai
authors: 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.
authors: Jonghwan
authors: J
authors: Kim
authors: Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Erik P
authors: EP
authors: Sulman
authors: 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.
authors: Shi-Yuan
authors: SY
authors: Cheng
authors: 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.
authors: L James
authors: LJ
authors: Lee
authors: Department of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
authors: Mitsutoshi
authors: M
authors: Nakada
authors: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors: Denis
authors: D
authors: Guttridge
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242, USA.
authors: Biplab
authors: B
authors: DasGupta
authors: Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors: Violaine
authors: V
authors: Goidts
authors: Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Krishna P
authors: KP
authors: Bhat
authors: 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.
authors: Ichiro
authors: I
authors: Nakano
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D020868:Gene Silencing; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D020930:MAP Kinase Kinase Kinases; C582627:MAP3K21 protein, human
keywords: cancer stem cell; epithelial-to-mesenchymal transition; glioblastoma; proneural-mesenchymal transition