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

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Citation

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. 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

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PMID: 26859459

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