KLF6 depletion promotes NF-κB signaling in glioblastoma.
Dysregulation of the NF-κB transcription factor occurs in many cancer types. Krüppel-like family of transcription factors (KLFs) regulate the expression of genes involved in cell proliferation, differentiation and survival. Here, we report a new mechanism of NF-κB activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-κB pathway and consequently reduces NF-κB nuclear localization and downregulates NF-κB targets. Reconstitution of KLF6 attenuates their malignant phenotype and induces neural-like differentiation and senescence, consistent with NF-κB pathway inhibition. KLF6 is heterozygously deleted in 74.5% of the analyzed glioblastomas and predicts unfavorable patient prognosis suggesting that haploinsufficiency is a clinically relevant means of evading KLF6-dependent regulation of NF-κB. Together, our study identifies a new mechanism by which KLF6 regulates NF-κB signaling, and how this mechanism is circumvented in glioblastoma through KLF6 loss.
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
A P
AP
Masilamani
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
R
R
Ferrarese
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
E
E
Kling
Department of Radiation Oncology, UAB Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
N K
NK
Thudi
Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
H
H
Kim
Department of Preventive Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University School of Medicine, Chicago, IL, USA.
D M
DM
Scholtens
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
F
F
Dai
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
M
M
Hadler
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
T
T
Unterkircher
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
L
L
Platania
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
A
A
Weyerbrock
Institute of Neuropathology, University of Freiburg, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
M
M
Prinz
Department of Neurosurgery, UAB Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
G Y
GY
Gillespie
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
G R
GR
Harsh
Department of Radiation Oncology, UAB Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
M
M
Bredel
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
M S
MS
Carro
D045744:Cell Line, Tumor; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D057895:Haploinsufficiency; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015533:Transcriptional Activation
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins