Role of KLF6 in shaping macrophage inflammatory response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA562566 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10042200.fastq.gz | Fastqsanger.gz | |||
| SRR10042201.fastq.gz | Fastqsanger.gz | |||
| SRR10042202.fastq.gz | Fastqsanger.gz | |||
| SRR10042203.fastq.gz | Fastqsanger.gz | |||
| SRR10042204.fastq.gz | Fastqsanger.gz |
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Project description:We examine the role of Klf6 in oligodendrocyte progenitor cells and determine that Klf6 acts in part through direct regulation of gp130 signaling and nuclear import via importin-α5 (Impα5), a key controller of nuclear trafficking.
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Project description:Gene-expression profiles of liver and hepatocellular carcinoma induced by diethylnitrosamine (DEN) in KLF6 +/- and wild type KLF6 mice. Inactivation of the KLF6 tumor suppressor is common in HCC due to hepatitis C virus (HCV), consistent with its anti-proliferative activity in HCC-derived cell lines and in hepatocytes of transgenic mice. We have evaluated the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis. In patients with surgically resected HCC, those with significantly reduced tumor expression of KLF6 had a significantly decreased survival. We modeled this event in KLF6 +/- mice, which displayed significantly more tumorigenicity than KLF6 +/+ animals in response to the hepatic carcinogen DEN, associated with recapitulation of gene signatures in both surrounding tissue and tumors that are associated with aggressive human HCCs. In DNA microarrays, mdm2 mRNA expression was increased in tumors from KLF6 +/- compared to KLF6 +/+ mice, which was validated by realtime qPCR and Western blot in both human HCC and DEN-induced murine tumors. Moreover, chromosomal immunoprecipitation and co-transfection assays established the P2 intronic promoter of mdm2 as a bona fide transcriptional target repressed by KLF6. Whereas KLF6 over-expression in HCC cell lines led to reduced MDM2 levels and increased p53 protein and transcriptional activity, reduction in KLF6 by siRNA led to increased MDM2 and reduced p53. Our findings indicate that KLF6 deficiency contributes significantly to the carcinogenic milieu in human and murine HCC, and uncover a novel tumor suppressor activity of KLF6 in HCC, by linking its transcriptional repression of MDM2 to stabilization of p53. Keywords: Liver, Hepatocellular carcinoma, Expression array, Exon array, Affymetrix KLF6 +/- mice were previously generated by homologous recombination in which exon 2 was targeted using an 11-kb targeting construct, and replaced with neomycin/lacZ cassette. After selection with neomycin, the ES clones were injected into C57BL/6 mouse blastocysts and implanted into pseudo pregnant females; two lines of KLF6 +/- mice were generated from the resulting chimeric animals (Blood 107;1357, Oncogene 26;4428). Whereas KLF6 -/- mice are embryonic lethal, KLF6 +/- animals had no demonstrable abnormalities in the absence of any stressor. Male KLF6 +/- mice were bred with wild type C57BL/6 to generate mixed litters of KLF6 +/- and KLF6 +/+ animals. Progeny were genotyped using PCR-amplified tail DNA, using primers as previously described (Oncogene 26;4428). Amplified fragments were separated on a 2.5% agarose gel, revealing bands of ~200 bp (wild type KLF6) and ~100 bp (Neo), as expected. At 2 weeks of age, KLF6 +/+ and KLF6 +/- mice were injected intraperitoneally with either a single dose of diethyl nitrosamine (DEN), 5 µg/g body weight in 100 µl of saline, or vehicle alone. Vehicle and DEN-treated mice were maintained on standard chow, and then sacrificed 3, 6 or 9 months later. At the time of sacrifice the animals were weighed, and blood and liver samples were harvested for analysis and tumor quantification.
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Project description:The PDGF and mTOR pathways are clinically relevant therapeutic targets in clear cell renal cell carcinoma (ccRCC), but the molecular mechanisms that lead to their activation has remained poorly understood. By chromatin and transcriptomic profiling and functional analysis we have identified Kruppel like factor 6 (KLF6), a transcription factor of the zinc-finger family, as a critical regulator of the PDGF-mTOR axis in ccRCC. KLF6 expression is supported by one of the strongest super enhancers in ccRCC cells. Inhibition of KLF6 in several ccRCC cell lines impaired cell proliferation in vitro and in vivo and reduced metastatic lung colonization. KLF6 depletion led to downregulation of lipid homeostasis pathways downstream of SREBF1 and SREBF2, suggesting a role for KLF6 as a regulator of mTOR. We find that KLF6 modulates mTORC1 activity in ccRCC via transcriptionally regulating the expression of PDGFB, an activator of the PIK3-AKT-mTOR signalling pathway. Targeting PDGFB in ccRCC inhibited mTORC1, and supplementing KLF6-depleted cells with recombinant PDGFB rescued mTORC1 activity. Our data suggest that a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway, supports an autocrine PDGFB-dependent signalling loop that promotes mTOR activity in ccRCC. These results suggest the possibility that combining low dose PDGFR and mTOR inhibition could be a viable therapeutic strategy for ccRCC.
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