ArticleCancer cell2016
Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner.
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Article in Cancer cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers, 1 of them a synthesis that pooled it.
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107citing papers in PubMed, 1 pooled it
12.5field-weighted citation impact, top 1% of its field
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Who cites it
107 citing papers in PubMed, 1 synthesis or guideline pooled it, 154 citations in OpenAlex.
- Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies.International journal of molecular sciences · 2023Pooled it
- Targeting LDHA Palmitoylation Sensitizes GBM to Chemoradiotherapy via Suppressing Palmitic Acid Induced Glycolytic Reprogramming.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Uncovering the signaling networks of disseminated glioblastoma cells in vivo with INSIGHT.Nature communications · 2026Article
- Positive TAZ-TDG feedback loop drives proneural-to-mesenchymal transition to promote glioblastoma progression.Journal of translational medicine · 2026Article
- Integrated 2D-3D Proteomic Profiling Identifies MLK4 as a Microenvironment-Responsive Regulator of Chemotherapeutic Resistance in Human Glioblastoma Cells.Biology of the cell · 2026Article
- MLK4 orchestrates macrophage-induced triple-negative breast cancer invasion and ECM remodeling via enhanced paracrine signaling and NF-κB-MMP axis activation.Cell death & disease · 2026Article
- Identification of a Novel Radiosensitivity-Related Signature and Validation of GPX8 in Regulating the Radiosensitivity of Glioma.CNS neuroscience & therapeutics · 2026Article
- NAT10-mediated N4-acetylcytidine (ac4C) modification of PIK3R2 mRNA promotes malignant progression of glioblastoma.Cell death & disease · 2025Article
- Phenotypic variations in glioma stem cells: regulatory mechanisms and implications for therapeutic strategies.Journal of translational medicine · 2025Review
- The Pivotal Role of NF-κB in Glioblastoma: Mechanisms of Activation and Therapeutic Implications.International journal of molecular sciences · 2025Review
- Article
- Regulatory role of circular RNAs in the development of therapeutic resistance in the glioma: A double-edged sword.Iranian journal of basic medical sciences · 2025Review
- NF-κB role on tumor proliferation, migration, invasion and immune escape.Cancer gene therapy · 2024Review
- Long non-coding RNA lung cancer-associated transcript-1 promotes glioblastoma progression by enhancing Hypoxia-inducible factor 1 alpha activity.Neuro-oncology · 2024Article
- Cancer stem cells: advances in knowledge and implications for cancer therapy.Signal transduction and targeted therapy · 2024Review
- Humanin activates integrin αV-TGFβ axis and leads to glioblastoma progression.Cell death & disease · 2024Article
- UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.Cellular and molecular life sciences : CMLS · 2024Article
- Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.Nature cell biology · 2024Article
- Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition.Cancer biology & medicine · 2024Review
- miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition.iScience · 2024Article
47 more citing papers are in PubMed but not listed here.
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Authors and funding
27 authors at 11 institutions in 3 countries.
Sung-Hak KimDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Ravesanker EzhilarasanDepartment of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Emma PhillipsDivision of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
Daniel Gallego-PerezDepartment 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.
Amanda SparksDepartment of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
David TaylorDepartment of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Katherine LadnerHuman Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Takuya FurutaDepartment of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
Hemragul SabitDepartment of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
Rishi ChhipaDivision of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242, USA.
Ju Hwan ChoDepartment of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Ahmed MohyeldinDepartment of Neurosurgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Samuel BeckDepartment 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.
Kazuhiko KurozumiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Toshihiko KuroiwaDepartment of Neurosurgery, Osaka Medical College, Osaka 569-8686, Japan.
Ryoichi IwataDepartment of Neurosurgery, Kansai Medical University, Osaka 573-1191, Japan.
Akio AsaiDepartment of Neurosurgery, Kansai Medical University, Osaka 573-1191, Japan.
Jonghwan KimDepartment 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.
Erik P SulmanDepartment of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Shi-Yuan ChengThe 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.
L James LeeCenter 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.
Mitsutoshi NakadaDepartment of Neurosurgery, Kanazawa University, Kanazawa 920-8641, Japan.
Denis GuttridgeHuman Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Biplab DasGuptaDivision of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242, USA.
Violaine GoidtsDivision of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
Krishna P BhatDepartment of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Ichiro NakanoDepartment 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.
The Ohio State University · USKanazawa University · JPThe University of Texas MD Anderson Cancer Center · USCincinnati Children's Hospital Medical Center · USGerman Cancer Research Center · DEKansai Medical University · JPThe University of Texas at Austin · USUniversity of Alabama at Birmingham · USNorthwestern University · USOkayama University · JPOsaka Medical and Pharmaceutical University · JP
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MTumor Environment and Metastasis (TEAM) Research ProgramP30CA060553 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Daniela E Matei · 1993 to 2026
$153.9MTranslational Therapeutics Research Program (TT)P30CA016058 · NCI · OHIO STATE UNIVERSITY · PI Tasleem J Padamsee · 1985 to 2026
$132.3MTropism Enhanced Oncolytic Adenovirus for the Treatment of Brain TumorsP50CA127001 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Juan Fueyo · 2008 to 2026
$41.2MLCenter for Clinical and Translational Science and TrainingUL1TR001425 · NCATS · UNIVERSITY OF CINCINNATI · PI MEINZEN-DERR, JAREEN, STRAWN, JEFFREY ROBERT · 2015 to 2024
$37.5MThe Tumor Microenvironmental Barrier to Effective Viral OncolysisP01CA163205 · NCI · OHIO STATE UNIVERSITY · PI MICHAEL A CALIGIURI · 2013 to 2026
$26.0MThe unique roles of the GTP-binding/protein crosslinking enzyme transglutaminase-2 and signaling partners in aggressive cancersR01CA201402 · NCI · CORNELL UNIVERSITY · PI CERIONE, RICHARD A. · 2016 to 2024
$4.3MOhio State University DISCOVERY PREP for Biomedical ResearchR25GM089571 · NIGMS · OHIO STATE UNIVERSITY · PI ASKWITH, CANDICE C, GLASPER, ERICA R · 2010 to 2024
$3.5MMetabolism Informs Intertumoral & Intratumoral HeterogeneityR01NS087913 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI NAKANO, ICHIRO, RICH, JEREMY N · 2014 to 2018
$2.0MGlioblastoma Phenotype Modulation Through miRNA Control of Wnt SignalingR01NS093843 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI CHENG, SHI-YUAN · 2015 to 2019
$1.8MModulation of Oncogenic Signaling in GlioblastomasR01CA159811 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI CHENG, SHI-YUAN · 2012 to 2016
$1.8MAutophagy Regulation of Glioblastoma Tumorigenesis and Responses to TherapyR01NS095634 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI CHENG, SHI-YUAN · 2015 to 2019
$1.7MNCATS NIH HHS UL1 TR001425NCI NIH HHS 2P50CA1270011NCI NIH HHS NIH/NCI P01 CA163205NCI NIH HHS NIH R01CA158911NCI NIH HHS P01 CA163205NCI NIH HHS P30 CA016058NCI NIH HHS P30 CA016672NCI NIH HHS P30 CA060553NCI NIH HHS P50 CA127001NCI NIH HHS R01 CA159811NCI NIH HHS R01 CA183991NCI NIH HHS R01 CA201402NCI NIH HHS R21 CA175875NIGMS NIH HHS R25 GM089571NINDS NIH HHS NIH/NINDS 1R01NS0 75291-01NINDS NIH HHS NIH/NINDSR01 NS083767NINDS NIH HHS NS093843NINDS NIH HHS NS095634NINDS NIH HHS R01 NS083767NINDS NIH HHS R01 NS087913NINDS NIH HHS R01 NS093843NINDS NIH HHS R01 NS095634
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.
Indexed as
AnimalsApoptosisBrain NeoplasmsGene SilencingGliomaHumansMAP Kinase Kinase KinasesMesenchymal Stem CellsMiceNeoplastic Stem CellsNF-kappa BPhosphorylationSignal TransductionMAP3K21 protein, humanMAP Kinase Kinase KinasesNF-kappa Bcancer stem cellepithelial-to-mesenchymal transitionglioblastomaproneural-mesenchymal transition
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