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Loss of Function of Krüppel-like Factor 6 Promotes Nuclear Factor-kB Signaling in Glioblastoma

Anie Priscilla Masilamani, Department of Neurozentrum, Uniklinik Freiburg, Germany; Thomas Unterkircher, Department of Neurozentrum, Uniklinik Freiburg, Germany; Roberto Ferrarese, Department of Neurozentrum, Uniklinik Freiburg, Germany; Eva Bug, Department of Neurozentrum, Uniklinik Freiburg, Germany; Leonardo Platania, Department of Neurozentrum, Uniklinik Freiburg, Germany; Markus Bredel, Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA; Maria Stella Carro, Department of Neurozentrum, Uniklinik Freiburg, Germany;


The transcription factor nuclear factor-B (NF-B) plays an important role in tumorigenesis. In tumor cells, NF-B is activated by mutations in its genes or in genes controlling its activity. By two independent in silico approaches we have identified Krüppel-like family transcription factor 6 (KLF6) as a putative regulator of NF-B negative regulators NFKBIA, TNFAIP3, TNIP1, and TNIP2. KLFs regulate expression of genes involved in cell proliferation, differentiation, and survival. Here we report a new mechanism of NF-B activation in glioblastoma through loss of function of KLF6. We show that KLF6 transactivates multiple genes controlling the NF-B pathway and that haploinsufficiency is a clinically relevant means of evading KLF6-dependent regulation of NF-B. We overexpressed full length KLF6 (KLF6-wt) or its oncogenic variant (KLF6-SV1) in LN229 glioblastoma cells and primary tumor-derived cell line BTSC23 and observed that KLF6-wt is able to transactivate the expression of the four NF-kB regulators. By Chromatin immunoprecipitation, we confirmed binding of KLF6-wt to all four gene promoters. Moreover, real-time RT-PCR and immunoblotting showed increased expression of all four NF-B control genes upon KLF6-wt overexpression. We show that reconstitution of KLF6-wt in LN229 cells and in a primary Glioblastoma cell line inhibits NF-B, attenuates the malignant phenotype of glioblastomas, and induces neuronal differentiation and senescence. Overall our data show a mechanistic link between KLF6-wt and NF-B regulation, which leads to increased NF-B signaling during tumorigenesis. These new molecular insights into the complex mechanisms that promote NF-B signaling during human carcinogenesis also provide prognostic insight and inform the search for effective therapy.

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