| Literature DB >> 26859459 |
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.
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.Entities:
Keywords: cancer stem cell; epithelial-to-mesenchymal transition; glioblastoma; proneural-mesenchymal transition
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Year: 2016 PMID： 26859459 PMCID： PMC4837946 DOI： 10.1016/j.ccell.2016.01.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743