Integrated omics profiling reveals FOXA1 and Ku70/Ku80 as the direct target of ivermectin for prostate carcinogenic inhibition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA716321 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14037500_1.fastq.gz | Fastqsanger.gz | |||
| SRR14037500_2.fastq.gz | Fastqsanger.gz | |||
| SRR14037501_1.fastq.gz | Fastqsanger.gz | |||
| SRR14037501_2.fastq.gz | Fastqsanger.gz | |||
| SRR14037502_1.fastq.gz | Fastqsanger.gz |
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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: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:Ivermectin is a widely used antiparasitic drug and shows promising anticancer activity in various cancer types. Although multiple signaling pathways modulated by ivermectin have been identified in tumor cells, few studies have focused on the exact target of ivermectin. Herein, we report the pharmacological effects and targets of ivermectin in prostate cancer. Ivermectin caused G0/G1 cell cycle arrest, induced cell apoptosis and DNA damage, and decreased androgen receptor (AR) signaling in prostate cancer cells. Further in vivo analysis showed ivermectin could suppress 22RV1 xenograft progression. Using integrated omics profiling, including RNA-seq and thermal proteome profiling, the forkhead box protein A1 (FOXA1) and non-homologous end joining (NHEJ) repair executer Ku70/Ku80 were strongly suggested as direct targets of ivermectin in prostate cancer. The interaction of ivermectin and FOXA1 reduced the chromatin accessibility of AR signaling and the G0/G1 cell cycle regulator E2F1, leading to cell proliferation inhibition. The interaction of ivermectin and Ku70/Ku80 impaired the NHEJ repair ability. Cooperating with the downregulation of homologous recombination repair ability after AR signaling inhibition, ivermectin increased intracellular DNA double-strand breaks and finally triggered cell death. Our findings demonstrate the anticancer effect of ivermectin in prostate cancer, indicating that its use may be a new therapeutic approach for prostate cancer.
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Project description:Ku80/Ku70 complex associated RNA in HEK293T cells
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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: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.
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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.
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2012-09-13 | E-GEOD-32104 | biostudies-arrayexpress