Abstract
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.
Original language | English (US) |
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Pages (from-to) | 3562-3575 |
Number of pages | 14 |
Journal | Oncogene |
Volume | 36 |
Issue number | 25 |
DOIs | |
State | Published - Jun 22 2017 |
Funding
This study was supported by National Cancer Institute grant P20 CA151129-01A1/UAB Specialized Program of Research Excellence (SPORE) in Brain Cancer (M Bredel), German Cancer Aid Grant Award (107714, M Bredel), State of Alabama Investment Pool for Action (IMPACT) funds (M Bredel).
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research