Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
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ABSTRACT:
PROVIDER: PRJNA674039 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR12971074.fastq.gz | Fastqsanger.gz | |||
| SRR12971075.fastq.gz | Fastqsanger.gz |
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Project description:BackgroundUrothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. However, the molecular mechanism of how CPH inhibits tumor progression is not fully understood.MethodsGenes that were upregulated after treatment with CPH in UC cells, were examined by RNA-Seq. Real-time quantitative PCR (RT-qPCR) was employed to detect IRF6 expression while COBRA assay and bisulphite pyrosequencing were used to examine promoter methylation of IRF6. Enrichment of total H3K27 acetylation and H3K4 mono-methylation were detected by western blotting. Colony formation and flow cytometry were used to examine proliferation and apoptosis in UC cells overexpressed or depleted with IRF6. Nude mice xenograft model was used to examine the effect of IRF6 in UC.ResultsOur result showed that several genes, including IRF6 were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, probably due to promoter hypomethylation and enrichment of H3K27 acetylation and H3K4 mono-methylation. These results may be due to the fact that CPH could alter the activity, but not the expression of epigenetic modifiers. Finally, re-expression of IRF6 in UC inhibited tumor growth in vitro and in an xenograft mouse model, by inducing apoptosis.ConclusionIn conclusion, our results suggested that CPH may be an epigenetic modifier, modulating the expression of the potential tumor suppressor IRF6, in inhibiting tumor growth in UC.
| S-EPMC8054409 | biostudies-literature
Project description:To investigate the effect of cyproheptadine treatment on bladder cancer cells, expression profile was compared in BFTC905 cells treatment DMSO vs 55µM CPH.
2021-04-08 | GSE160703 | GEO
Project description:The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.
2019-08-29 | GSE124047 | GEO
Project description:The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.
2019-08-29 | GSE127341 | GEO
Project description:The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.
2019-08-29 | GSE127338 | GEO
Project description:The transcription factor Interferon Regulatory Factor 6 (IRF6) is crucially involved in craniofacial development and regulates the proliferation/differentiation balance in keratinocytes. Pathological IRF6 variants have been found in Van der Woude syndrome (VWS), the most common syndromic form of cleft lip / palate (CLP) as well as in non-syndromic CLP cases. Besides its prominent function in regulating keratinocyte differentiation, recent data revealed that IRF6 is also involved in wound healing and migration. Since a significant fraction of CLP patients undergoing corrective cleft surgery experience wound healing complications, IRF6 represents an interesting candidate gene linking the two processes. However, Irf6 function has been mainly studied in mice and knowledge on IRF6 in human cells remains sparse. Here, we aimed to elucidate the role of IRF6 in human postnatal skin- and oral mucosa-derived keratinocytes by its ablation using CRISPR/Cas9. We complement this approach by applying proteomics and identify that lack of IRF6 disrupts human epithelial homeostasis by altering cell colony morphology, migration pattern, and the differentiation potential of keratinocytes.
2022-02-17 | PXD027669 | Pride
Project description:The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.
2019-08-29 | GSE124048 | GEO
Project description:Loss of Irf6 leads to disruption of branching morphogenesis and secretory acnii formation in salivary gland. To determine the differentially expressed genes in Irf6 mutant, embryonic salivary gland tissues were extracted at E14.5.
2017-07-29 | GSE102020 | GEO
Project description:Gastrulation initiates with the formation of the primitive streak, during which, cells of the epiblast delaminate to form the mesoderm and definitive endoderm. At this stage, the pluripotent cell population of the epiblast undergoes very rapid cellular proliferation and extensive epigenetic programming. Here, we show that Fam208a, a new epigenetic modifier, is essential for early post-implantation development using mouse strains harbouring two different allelic mutations. We show that at E6.5, Fam208a mutants have a decreased number of Oct4-positive epiblast cells due to an increase in p53-driven apoptosis. Complete removal of p53 could rescue the gastrulation block in Fam208a mutants, enabling them to develop until E8.5-9.0. The data demonstrates a new in vivo function of Fam208a in maintaining epiblast fitness thereby, making it an important factor at the onset of gastrulation.
2017-06-01 | E-MTAB-5357 | biostudies-arrayexpress
Project description:Transcription factor paralogs may share a common role (e.g. Hox) in staged or overlapping expression in specific tissues. In other examples, members have distinct roles in a range of embryologic, differentiation or response pathways (e.g. Tbx, Pax). For the Interferon Regulatory Factor (IRF) family of transcription factors, mice deficient in Irf1, Irf2, Irf3, Irf4, Irf5, Irf7, Irf8 or Irf9, have defects in the immune response but display no embryologic abnormalities. Mice deficient for Irf6 have not been reported, but in humans, mutations in IRF6 cause two Mendelian orofacial clefting syndrome, and genetic variation in IRF6 confers risk for isolated cleft lip and palate. Mice deficient for Irf6 have abnormal skin, limb and craniofacial development. Histological and gene expression analyses indicate that the primary defect is in keratinocyte differentiation and proliferation. This study describes a novel role for an IRF family member in epidermal development. Experiment Overall Design: Skin from E17.5 mice was removed and flash frozen for RNA extraction and hybridization on Affymetrix microarrays.
2007-11-13 | E-GEOD-5800 | biostudies-arrayexpress