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 ChengL. James Lee, Mitsutoshi Nakada, Denis Guttridge, Biplab DasGupta, Violaine Goidts, Krishna P. Bhat, Ichiro Nakano

Research output: Contribution to journalArticlepeer-review

121 Citations (Scopus)


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. Kim et al. show that stem-like cells of mesenchymal (MES) glioblastoma (GSCs) overexpress MLK4 and that silencing MLK4 reduces GSCs self-renewal, radioresistance, and tumorigenicity. IKKα is a MLK4 substrate and targeting the MLK4-driven NF-κB signaling could be a therapeutic strategy for MES glioblastoma.

Original languageEnglish
Pages (from-to)201-213
Number of pages13
JournalCancer Cell
Issue number2
Publication statusPublished - Feb 8 2016


  • Cancer stem cell
  • Epithelial-to-mesenchymal transition
  • Glioblastoma
  • Proneural-mesenchymal transition

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research


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