Integrated omics profiling reveals FOXA1 and Ku70/Ku80 as the direct target of ivermectin for prostate carcinogenic inhibition
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PROVIDER: PRJNA716321 | ENA |
REPOSITORIES: ENA
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Project description:Here, we show that ivermectin suppress prostate cancer progression by inhibiting AR signaling pathway and attenuate cellular DNA damage repair capacity. We applied an integrated omics profiling including RNA-seq and Thermal proteome, that found pioneer factor Forkhead Box Protein A1 (FOXA1) and Non-homologous End Joining (NHEJ) repair executer Ku70/Ku80 was the direct target of Ivermectin in prostate cancer. Ivermectin binds to these two proteins and block their biological function, which results in blockade of AR signaling transcription and deficiency of DNA double-strand breaks (DSBs) repair system, and thereby leads to G0/G1 arrest and trigger synthetic lethality Our findings demonstrate both the effect and target of Ivermectin in prostate cancer comprehensively and systemically, indicating that use of Ivermectin may constitute a new therapeutic approach for prostate cancer.
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Project description:We report the Ku80/Ku70 complex associated RNA in HEK293T cells using RNA-seq following PAR-Clip.
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Project description:DNA-PK is a heterotrimeric complex that consists of Ku70 (XRCC6), Ku80 (XRCC5) and DNA-PKcs (PRKDC) subunits. DNA-PK complex is a major player in DNA double strand break (DSB) repair via non-homologous end joining pathway. This process requires all of DNA-PK subunits. Ku70/Ku80 heterodimers firstly bind to DNA-ends at DSB, that increase affinity of DNA-PKcs to DNA-ends. Recruitment of DNA-PKcs subunit to DSB leads to phosphorylation events near DSB, recruitment of another NHEJ-related genes that restore DNA integrity. However, today a lot of evidence demonstrate participation of DNA-PK components in other cellular process, e.g. cytosolic DNA sensing, apoptosis regulation, cellular movement and adhesion. It is important to note that not all subunits of DNA-PK complex are necessary for these process. This demonstrate the independent functions of DNA-PK subunits. Here we for the first time using NGS-sequencing analyzed the transcriptional changes in HEK293T cells under depletion of Ku70, Ku80 or DNA-PKcs to characterize the independent functions of each subunit.
2021-07-23 | GSE180581 | GEO
Project description:Many metabolism-related genes undergo alternative splicing to generate circular RNAs although their functions remain poorly understood. Here we report that circPRKAA1, a circRNA derived from the α1 subunit of AMPK, fulfils a fundamental role in maintaining lipid homeostasis. CircPRKAA1 expression facilitates fatty acid synthesis and promotes lipid storage through two coordinated functions. First, circPRKAA1 promotes a tetrameric complex between the Ku80/Ku70 heterodimer and the mature form of sterol regulatory element-binding protein-1 (mSREBP1) to enhance the stability of mSREBP1. Secondly, circPRKAA1 selectively binds to the promoters of the ACC1, ACLY, SCD1 and FASN genes to recruit mSREBP1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. Moreover, circPRKAA1 biogenesis is negatively regulated by AMPK activity with lower AMPK activation in hepatocellular carcinoma tissues frequently associated with elevated circPRKAA1 expression. Together, this work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells.
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Project description:Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces Type-I IFN production. We found that transfection of different types of DNA into various untreated cells induces Type-III IFN (IFN-lambda1) rather than Type-I IFN, indicating the presence of uncharacterized DNA sensor(s). A pull-down assay using cytosolic proteins identified that Ku70 and Ku80 are the DNA binding proteins. The knockdown studies and the reporter assay revealed that Ku70 is a novel DNA sensor inducing the IFN-lambda1 activation. The functional analysis of IFNL1 promoter revealed that PRDI and ISRE sites are predominantly involved in the DNA-mediated IFNL1 activation. A pull-down assay using nuclear proteins demonstrated that the IFN-lambda1 induction is associated with the activation of IRF-1 and IRF-7. This is the first report of a specific induction of Type-III rather than Type-I IFN and of Ku70 that plays a key role in the activation of innate immune responses. To identify the nature of the anti-HIV mediators associated with the empty vector transfection, we compared patterns of gene expression between untreated and pCMV9-transfected HEK293 cells, using DNA microarray analysis.
2011-01-29 | E-GEOD-26944 | biostudies-arrayexpress
Project description:Targeting an engineered DNA fragment to a specific site in chromosomes in order to disrupt, overexpress or modify the nucleotide sequence of a gene requires homologous recombination repair mechanism. This DNA repair mechanism is not predominant in fungi, resulting in extremely low targeting efficiency. To increase this efficiency, it is becoming common practice to disable the non homologous end joining (NHEJ) pathway that causes random integration, by deleting homologous gene to human KU70 and KU80 which encode proteins functioning in the NHEJ pathway. These genes have been successfully deleted in several organisms, including the yeast Kluyveromyces lactis and the fungi Neurospora Crassa and several Aspergilli species. In this study we investigated the behavior of high penicillinG-producing Penicillium chrysogenum strains, in which the KU70 or KU80 homologues, HdfA or HdfB, had been deleted. Targeting efficiency in these mutant strains was significantly increased relative to the reference strain. Both physiological and transcriptome data of chemostat cultivations of the hdfA deletion strain and the reference strain showed minimal differences. However, in a direct competition experiment to assess global strain fitness, the reference strain had a clear advantage over the deletion strain. The full characterization of these recombinant host strains is an essential step to guide the future construction of a whole genome knock-out mutant collection.
2009-03-09 | GSE12893 | GEO
Project description:Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces Type-I IFN production. We found that transfection of different types of DNA into various untreated cells induces Type-III IFN (IFN-lambda1) rather than Type-I IFN, indicating the presence of uncharacterized DNA sensor(s). A pull-down assay using cytosolic proteins identified that Ku70 and Ku80 are the DNA binding proteins. The knockdown studies and the reporter assay revealed that Ku70 is a novel DNA sensor inducing the IFN-lambda1 activation. The functional analysis of IFNL1 promoter revealed that PRDI and ISRE sites are predominantly involved in the DNA-mediated IFNL1 activation. A pull-down assay using nuclear proteins demonstrated that the IFN-lambda1 induction is associated with the activation of IRF-1 and IRF-7. This is the first report of a specific induction of Type-III rather than Type-I IFN and of Ku70 that plays a key role in the activation of innate immune responses.
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Project description:The normally virulent type-I RH parasite is rendered avirulent when lacking ROP5. The avirulent phenotype is a consequence of interaction with the host innate immune system. We sought to understand if ROP5 alters host gene expression in order to escape host defenses. We saw no gene expression differences between host cells infected with wt (RH?ku80) or RH?ku80?rop5 parasites. We have included uninfected HFF samples that were harvested in parallel with the infected samples. Host gene expression in response to infection with Toxoplasma gondii. Two independent samples per sample type. Three sample types: HFF infected with RH?ku80, HFF infected with RH?ku80?rop5, and uninfected HFF.
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Project description:Transcriptome data for HEK293T cells depleted of one subunit of DNA-PK complex: Ku70, Ku80 or DNA-PKcs.
| PRJNA748741 | ENA
Project description:batch culture of Yarrowia lipolytica strain E150 delta-Ku70
2012-12-31 | E-MTAB-940 | biostudies-arrayexpress