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KLF6 depletion promotes NF-?B signaling in glioblastoma.

ABSTRACT: Dysregulation of the NF-?B 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-?B activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-?B pathway and consequently reduces NF-?B nuclear localization and downregulates NF-?B targets. Reconstitution of KLF6 attenuates their malignant phenotype and induces neural-like differentiation and senescence, consistent with NF-?B 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-?B. Together, our study identifies a new mechanism by which KLF6 regulates NF-?B signaling, and how this mechanism is circumvented in glioblastoma through KLF6 loss.

SUBMITTER: Masilamani AP 

PROVIDER: S-EPMC5485221 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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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 N  ...[more]

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