KDM5C represses FASN-mediated lipid metabolism to exert tumor suppressor activity in intrahepatic cholangiocarcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143781 | GEO | 2021/01/26
REPOSITORIES: GEO
Similar Datasets
Project description:Background: KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. However, the role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown. Methods: Expression levels of KDM5C in ICC patients were determined by qRT-PCR, western blotting and immunohistochemical assay. The functions of KDM5C in cell proliferation and invasion were determined in human ICC cells and mouse xenograft model using KDM5C overexpression and knockdown strategies in vivo. RNA-seq analysis was applied to investigate the transcriptional program of KDM5C. In addition, ChIP-qPCR was used to determine the regulation of FASN by KDM5C. Results: Here, we show that KDM5C was downregulated in human ICC, where its diminished expression was associated with poor prognosis. ICC cell proliferation and invasion were inhibited by KDM5C overexpression. Moreover, KDM5C suppressed ICC proliferation and metastasis in vivo. RNA-sequencing showed that KDM5C inhibits key signal pathways of cell proliferation, cell invasion and fatty acid metabolism. ChIP-qPCR revealed that overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of the expression of FASN, which represents the major target gene of KDM5C to mediate the proliferation and invasion of ICC cells. Conclusions: Our results revealed the role of KDM5C as a novel tumor suppressor in ICC largely by repressing FASN-mediated lipid acid metabolism and thus KDM5C may contribute to the pathogenesis of ICC.
| S-EPMC7344276 | biostudies-literature
Project description:KDM5C represses FASN-mediated lipid metabolism to exert tumor suppressor activity in intrahepatic cholangiocarcinoma
| PRJNA601669 | ENA
Project description:To characterize genome-wide KDM5C traget genes in HTR-8/SVneo cells transduced with KDM5C-expression vector by CUT&Tag.
2022-12-16 | GSE200540 | GEO
Project description:KDM5C is a H3K4- specific demethylase, which has multiple biological roles in development and disease. However, the role of KDM5C in trophoblasts at the maternal-fetal interface remains unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from patient with recurrent miscarriage (RM). Trophoblasts proliferation and invasion was inhibited by KDM5C overexpression and was enhanced by KDM5C knockdown. Interestingly, KDM5C knockdown promoted trophoblast invasion in villous explant culture system. RNA-seq and ChIP-seq analyses revealed that KDM5C exerts anti-proliferation and anti-invasion effect by directly modulating H3K4 methylation level to repress the expression of a number of key regulatory genes. We show that two of these genes, TGFβ2, RAGE, are essential for the proliferation and invasion of trophoblasts. Taken together, our results show that the KDM5C is regulator of trophoblast function during early pregnancy and indicated that KDM5C may be involved in the pathogenesis of RM. Next Generation Sequencing Facilitates Quantitative Analysis of HTR-8/SVneo cells transduced with control or KDM5C-expression vector, and HTR-8/SVneo cells transduced with NC or KDM5C shRNA-expression vector,
2022-12-16 | GSE141716 | GEO
Project description:To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of Cebpa mutant AML. This led to the identification of the Histone 3 Lysine 4 (H3K4) demethylase, KDM5C, as a novel tumor suppressor in AML. KDM5C potentially functions as a transcriptional repressor via its demethylase activity at promoters, and dysregulation could therefore have widespread consequences. Here, we found that reduced Kdm5c/KDM5C expression is associated with accelerated growth in both human and murine AML cell lines. In vivo, Kdm5c knockdown in a Cebpa mutant AML mouse model resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3 globally. This translated into the up-regulation of a group of bivalently marked immature genes, resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiation factors. Finally, we demonstrated that low levels of KDM5C were associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.
2023-03-10 | PXD016568 | Pride
Project description:KDM5C is a histone H3K4-specific demethylase, which has been shown to play a key role in biological disease and development. However, the role of KDM5C in trophoblasts at early pregnancy is currently unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from recurrent miscarriage (RM) patients compared with healthy controls (HCs). Trophoblast proliferation and invasion was inhibited by KDM5C overexpression and was promoted by KDM5C knockdown. Transcriptome sequencing revealed that elevated KDM5C exerted anti-proliferation and anti-invasion effects by repressing the expression of essential regulatory genes. The combination analysis of RNA-seq, ChIP-seq and CUT&Tag assay showed that KDM5C overexpression leads to the reduction of H3K4me3 on the promoters and the corresponding downregulation of expression of several regulatory genes in trophoblasts. Among these genes, TGFβ2 and RAGE are essential for the proliferation and invasion of trophoblasts. Importantly, overexpression of KDM5C by a systemically delivered KDM5C adenovirus vector (Ad-KDM5C) promoted embryo resorption rate in mouse. Our results support that KDM5C is an important regulator of the trophoblast function during early pregnancy, and suggesting that KDM5C activity could be responsible for epigenetic alterations seen RM disease. This SuperSeries is composed of the SubSeries listed below.
2022-12-16 | GSE141718 | GEO
Project description:KDM5C is a H3K4- specific demethylase, which has multiple biological roles in development and disease. However, the role of KDM5C in trophoblasts at the maternal-fetal interface remains unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from patient with recurrent miscarriage (RM). Trophoblasts proliferation and invasion was inhibited by KDM5C overexpression and was enhanced by KDM5C knockdown. Interestingly, KDM5C knockdown promoted trophoblast invasion in villous explant culture system. RNA-seq and ChIP-seq analyses revealed that KDM5C exerts anti-proliferation and anti-invasion effect by directly modulating H3K4 methylation level to repress the expression of a number of key regulatory genes. We show that two of these genes, TGFβ2, RAGE, are essential for the proliferation and invasion of trophoblasts. Taken together, our results show that the KDM5C is regulator of trophoblast function during early pregnancy and indicated that KDM5C may be involved in the pathogenesis of RM. To characterize genome-wide H3K4me3 chromatin-state of HTR-8/SVneo cells.
2022-12-16 | GSE141717 | GEO
Project description:The functional organization of eukaryotic genomes correlates with specific patterns of histone methylations. Regulatory regions in genomes like enhancers and promoters differ in their extent of methylation of histone H3 at lysine-4 (H3K4), but it is largely unknown how the different methylation states are specified and controlled. Here, we show that the Kdm5c/Jarid1c/SMCX member of the Kdm5 family of H3K4 demethylases can be recruited to both enhancer and promoter elements in embryonic stem cells and neuronal progenitor cells via gene-specific transcription factors. Knockdown of Kdm5c deregulates transcription via local increases in H3K4me3. Our data show that restricting H3K4me3 modification at core promoters dampens transcription, but Kdm5c is required at enhancers for their full activity. Remarkably, an impaired enhancer function activates the intrinsic promoter activity of Kdm5c-bound distal elements. Our results demonstrate that the Kdm5c demethylase plays a crucial and dynamic role in the functional discrimination between enhancers and core promoters. RNA from four independent cultures from each sh Kdm5c #1, sh Kdm5c #2 and non-targeting shRNA polyclonal cell lines were hybridized in dye-swap against a common reference of RNA from IB10 ES cells.
2013-04-05 | E-GEOD-38862 | biostudies-arrayexpress
Project description:Here, we show that the Kdm5c/Smcx member of the Jarid1 family of H3K4 demethylases is recruited to both enhancer and core promoter elements in ES and neuronal progenitor cells (NPC). Knockdown of Kdm5c deregulates transcription via a local increase in H3K4me3. While at core promoters the function of Kdm5c is to restrict transcription, loss of Kdm5c impairs enhancer function. Remarkably, an impaired enhancer function activates promoter activity from Kdm5c-bound intergenic regions. Our results demonstrate that the Kdm5c demethylase plays a crucial role in the functional identity and discrimination of enhancers and core promoters. We speculate that this is related to recruitment of H3K4me3 binders like the TFIID and NURF complexes6-8. Providing functional identity to genomic regions through balancing enzymes that deposit and remove histone modifications may prove to be a general epigenetic mechanism for the functional indexing of eukaryotic genomes. Examination of the KDM5C binding sites in mouse embryonic stem cells and in neuronal progenitor cells. Effect of KDM5C knock down on H3K4me3 and H3K4me1 levels and gene expression.
2013-04-01 | E-GEOD-34975 | biostudies-arrayexpress
Project description:RNA from four independent cultures from each sh Kdm5c #1, sh Kdm5c #2 and non-targeting shRNA polyclonal cell lines were hybridized in dye-swap against a common reference of RNA from IB10 ES cells
2013-04-05 | E-MTAB-1177 | biostudies-arrayexpress