TY - JOUR
T1 - Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner
AU - Kim, Sung Hak
AU - Ezhilarasan, Ravesanker
AU - Phillips, Emma
AU - Gallego-Perez, Daniel
AU - Sparks, Amanda
AU - Taylor, David
AU - Ladner, Katherine
AU - Furuta, Takuya
AU - Sabit, Hemragul
AU - Chhipa, Rishi
AU - Cho, Ju Hwan
AU - Mohyeldin, Ahmed
AU - Beck, Samuel
AU - Kurozumi, Kazuhiko
AU - Kuroiwa, Toshihiko
AU - Iwata, Ryoichi
AU - Asai, Akio
AU - Kim, Jonghwan
AU - Sulman, Erik P.
AU - Cheng, Shi Yuan
AU - Lee, L. James
AU - Nakada, Mitsutoshi
AU - Guttridge, Denis
AU - DasGupta, Biplab
AU - Goidts, Violaine
AU - Bhat, Krishna P.
AU - Nakano, Ichiro
N1 - Publisher Copyright:
© 2016 Elsevier Inc..
PY - 2016/2/8
Y1 - 2016/2/8
N2 - 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.
AB - 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.
KW - Cancer stem cell
KW - Epithelial-to-mesenchymal transition
KW - Glioblastoma
KW - Proneural-mesenchymal transition
UR - http://www.scopus.com/inward/record.url?scp=84958658738&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958658738&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2016.01.005
DO - 10.1016/j.ccell.2016.01.005
M3 - Article
C2 - 26859459
AN - SCOPUS:84958658738
SN - 1535-6108
VL - 29
SP - 201
EP - 213
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -