Loss of KDM6A enhances human pancreatic cancer progression and potentiates HDAC inhibitor lethality via restoring CDKN1A
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PROVIDER: PRJNA471502 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND & AIMS: Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of a histone modifier KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. METHODS: Immunohistochemical analysis of KDM6A was performed in 103 tumor specimens surgically resected from patients with PDAC. Cells knocked out for KDM6A by using the CRISPR/Cas9 system and expressing doxycycline-inducible KDM6A were established from each two human PDAC cell lines, respectively. RESULTS: Loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence-free and overall survival in the clinical samples. KDM6A knockout enhanced aggressive traits of human PDAC cell lines, whereas KDM6A overexpression suppressed them. Microarray analysis revealed reduced expression of 25 genes including five well-known tumor suppressors, such as CDKN1A, and ChIP-PCR analysis displayed depleted enrichment of histone H3 lysine 27 acetylation (H3K27ac) at the promoter regions of the five candidates. The epigenetic alterations were induced by the impaired recruitment of a histone acetyltransferase p300, which cooperatively interacted with KDM6A. Consistent with these results, the KDM6A knockout cells demonstrated higher vulnerability to histone deacetylase (HDAC) inhibitors through the reactivation of CDKN1A in vitro and in vivo than the KDM6A wild-type. CONCLUSIONS: KDM6A exhibited essential roles in human PDAC as a tumor suppressor. KDM6A deficiency could be a promising biomarker for unfavorable outcome in PDAC patients and a potential surrogate marker for response to HDAC inhibitors.
2020-01-30 | GSE114457 | GEO
Project description:The EZH2 histone methyltransferase is required for B cells to form germinal centers (GCs). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21Cip1). Deletion of Cdkn1a rescued the GC reaction in Ezh2 knockout mice. To study the effects of EZH2 in primary GC B cells we generated and validated a 3D B cell follicular organoid system that mimics the endogenous GC reaction. Using this system we found that depletion of EZH2 suppressed G1 to S phase transition of GC B cells in a Cdkn1a dependent manner. GC B cells of Cdkn1a;Ezh2 double knockout mice exhibited high levels of phospho Rb, indicating that loss of Cdkn1a allows progression of cell cycle. Moreover, we show that the transcription factor E2F1 plays a major role in inducing EZH2 upregulation during the GC reaction. E2F1 deficient mice manifest impaired GC responses, which was rescued by restoring EZH2 expression, thus defining a positive feedback loop whereby EZH2 controls GC B cell proliferation by suppressing CDKN1A, allowing cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1.
2017-08-10 | GSE95491 | GEO
Project description:CDKN1A plays multiple roles in distinctive biological processes, such as cellular proliferation, apoptosis, DNA repairing, and etc. In mouse, Cdkn1a deficiency led to cell arrest at G1 phase, and also reported that Cdkna1-deficient mice were susceptible to tumorigenesis. However, the functions of Cdkn1a in zebrafish were still elusive due to few studies. Our previous study indicated that Cdkn1a might be closely associated with folliculogenesis, and to further investigate its specific role during folliculogenesis, Cdkn1a was targeted disrupted by CRISPR/Cas9. Interestingly, Cdkn1a-deficient zebrafish were embryonic lethality, resulted in approximate 2% homozygous mutants in adult stage. Furthermore, homozygous mutants have accelerated follicle maturation that faster than WT, and were fertile at young age (2 month). However, the matured or large follicles in mutant soon become dysfunctional due to abnormal oocyte that led to infertile at 3 months. Gradually, the abnormal follicles were undertaken follicle degeneration, resulted in PG follicle enrichment in mutant ovary at 6 months. Similar follicle degeneration phenomenon was also observed in heterozygous mutant ovary at 8 months. The degenerating follicles in mutant were convinced by in situ apoptosis detection kit. To further explore molecular mechanism, RNA-seq and qPCR validation were adopted to identify underlying molecular pathway that involved in Cdkn1a deficient apoptosis. This study firstly reported the functions of Cdkn1a in zebrafish, particular in its critical role in maintenance of normal follicle development, and the special phenotypes in folliculogenesis perfectly interpretation of its dual roles on both proliferation and apoptosis at two different phases, which replenished its novel role in folliculogenesis that expanded our insights.
2024-10-27 | GSE239622 | GEO
Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.
2024-01-28 | PXD041254 | Pride
Project description:Here we show binding and occupancy profiles for KDM6A, H3K27me3 and H3K4me3 to address the epigenetic regulation of a subset of Rhox genes, Rhox6 and 9, in female and male ES cells during differentiation. To further address a functional role for KDM6A in the epigenetic regulation of Rhox6 and 9, binding profiles for female ES cells treated with a control siRNA and siRNA specific for Kdm6a are shown. We report that two members of the Rhox cluster, Rhox6 and 9, are regulated by de-methylation of histone H3 at lysine 27 by KDM6A, a histone demethylase with female-biased expression. Our results are consistent with other homeobox genes in that Rhox6 and 9 are in bivalent domains prior to embryonic stem cell differentiation and thus poised for activation. In female mouse ES cells KDM6A is specifically recruited to Rhox6 and 9 for gene activation, a process inhibited by Kdm6a knockdown. In contrast, KDM6A occupancy at Rhox6 and 9 is low in male ES cells and knockdown has no effect on expression. Our study implicates Kdm6a, a gene that escapes X inactivation, in the regulation of genes important in reproduction, suggesting that KDM6A may play a role in the etiology of developmental and reproduction-related effects of X chromosome anomalies. ChIP-chip was used to analyze the binding profiles of KDM6A, H3K27me3, and H3K4me3 during differentiation in female and male ES cells. Additionally, ChiP-chip of KDM6A binding in control treated and siRNA treated ES cells is presented.
2013-03-22 | E-GEOD-45390 | biostudies-arrayexpress
Project description:Purpose: The goals of this study are to compare 1. The transcription profile in KDM6A wildtype and KDM6A mutated urothelial bladder carcinoma. 2. The transcriptional changes in KDM6A mutated urothelial bladder carcinoma upon EZH2 inhibitor treatment.
2017-03-01 | GSE92723 | GEO
Project description:KAT6B overexpression rescues embryonic lethality in homozygous null KAT6A mice restoring vitality and normal lifespan [RNA-seq]
| PRJNA1211682 | ENA
Project description:KAT6B overexpression rescues embryonic lethality in homozygous null KAT6A mice restoring vitality and normal lifespan [CUT&TAG]
| PRJNA1211679 | ENA
Project description:We created isogenic mutiple myeloma and mouse embryonic fibroblast cell lines disrupted for KDM6A using CRISPR editing and Cre-mediated deletion. To detect KDM6A we inserted a dual HA tag sequence into the C-terminal of KDM6A by CRISPR-mediated editing. We also created one isogenic cell line harboring a jmjD-dead KDM6A where 2 amino acids essential for KDM6A enzymatic activity, H1146 and E1148 , were replaced with alanine residues
2024-10-01 | GSE244510 | GEO
Project description:Genome-wide studies characterizing mutational landscape of bladder cancer revealed the exceptionally high rate of chromatin modifier genes in bladder cancer. Thus, epigenetic deregulation is a critical theme which needs further investigation for bladder cancer research. One of the highly mutated genes in bladder cancer is KDM6A, functioning as H3K27 demethylase and part of MLL3/4 complexes. To decipher the role of KDM6A in normal vs tumor setting, we identified the genomic localization profiles of KDM6A in normal, immortalized and cancer bladder cells. Our results showed differential occupancy of KDM6A at the genes involved in cell differentiation, chromatin organization and Notch signaling depending on the cell type and the mutation status of KDM6A. Transcription factor motif analysis revealed an enrichment for HES1 for the KDM6A peaks identified for T24 bladder cancer cell line, which has a truncating mutation in KDM6A and lacking demethylase domain and also for the other clusters showing KDM6A localization. For the first time, using co-immunoprecipitation experiments, we show that KDM6A is in complex with TLE co-repressors and HES1, and illustrate the potential interaction of KDM6A with TLE co-repressors, HES1, RUNX, HHEX transcription factors by computational structural biology models. Our work makes important contributions to the understanding of KDM6A malfunction in bladder cancer and provides models for the functioning of KDM6A independent of its demethylase activity.
2023-03-03 | GSE216625 | GEO