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

Sung-Hak Kim; Ravesanker Ezhilarasan; Emma Phillips; Daniel Gallego-Perez; Amanda Sparks; David Taylor; Katherine Ladner; Takuya Furuta; Hemragul Sabit; Rishi Chhipa; Ju Hwan Cho; Ahmed Mohyeldin; Samuel Beck; Kazuhiko Kurozumi; Toshihiko Kuroiwa; Ryoichi Iwata; Akio Asai; Jonghwan Kim; Erik P Sulman; Shi-Yuan Cheng; L James Lee; Mitsutoshi Nakada; Denis Guttridge; Biplab DasGupta; Violaine Goidts; Krishna P Bhat; Ichiro Nakano

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

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

Authors

Sung-Hak Kim¹, Ravesanker Ezhilarasan², Emma Phillips³, Daniel Gallego-Perez⁴, Amanda Sparks⁵, David Taylor⁵, Katherine Ladner⁶, Takuya Furuta⁷, Hemragul Sabit⁷, Rishi Chhipa⁸, Ju Hwan Cho⁹, Ahmed Mohyeldin⁵, Samuel Beck¹⁰, Kazuhiko Kurozumi¹¹, Toshihiko Kuroiwa¹², Ryoichi Iwata¹³, Akio Asai¹³, Jonghwan Kim¹⁰, Erik P Sulman², Shi-Yuan Cheng¹⁴, L James Lee¹⁵, Mitsutoshi Nakada⁷, Denis Guttridge⁶, Biplab DasGupta⁸, Violaine Goidts³, Krishna P Bhat¹⁶, Ichiro Nakano¹⁷

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Brain Neoplasms / enzymology*
Brain Neoplasms / pathology
Gene Silencing
Glioma / enzymology*
Glioma / pathology
Humans
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / metabolism*
Mesenchymal Stem Cells / enzymology*
Mesenchymal Stem Cells / pathology
Mice
NF-kappa B / metabolism
Neoplastic Stem Cells / enzymology*
Neoplastic Stem Cells / pathology
Phosphorylation
Signal Transduction

Substances

NF-kappa B
MAP Kinase Kinase Kinases
MAP3K21 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding