| Autor: |
Masilamani, A P, Ferrarese, R, Kling, E, Thudi, N K, Kim, H, Scholtens, D M, Dai, F, Hadler, M, Unterkircher, T, Platania, L, Weyerbrock, A, Prinz, M, Gillespie, G Y, Harsh IV, G R, Bredel, M, Carro, M S |
| Zdroj: |
Oncogene; June 2017, Vol. 36 Issue: 25 p3562-3575, 14p |
| Abstrakt: |
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. |
| Databáze: |
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