Chromatin accessibility alterations in KDM6A-mutant bladder cancers
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PROVIDER: PRJNA805334 | ENA |
REPOSITORIES: ENA
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Project description:Chromatin accessibility alterations in KDM6A-mutant bladder cancers
| PRJNA805333 | ENA
Project description:Mutations in genes encoding critical epigenetic regulators are frequently noted in bladder cancer, however, the mechanisms by which these alterations impact the therapeutic response remain incompletely understood. Through retrospective analyses of multiple bladder cancer patient cohorts, we identified that loss-of-function mutations in KDM6A, a histone demethylase altered in approximately 26% of advanced bladder cancers, are associated with reduced overall survival following cisplatin-based chemotherapy whereas they correlate with improved outcomes with anti–PD-1/anti–PD-L1 therapy. To elucidate the biological underpinnings of this divergent clinical response, we conducted reverse translational mechanistic studies using human bladder cancer cell lines harboring mutations in KDM6A gene and CRISPR-Cas9–mediated deletion of Kdm6a in murine bladder cancer models. We found that KDM6A deficiency drives cisplatin resistance via increased generation of extrachromosomal circular DNA (eccDNA) carrying oncogenes linked to drug resistance. Additionally, KDM6A directly regulates DNA mismatch and double-strand break repair genes, and its loss impairs these pathways in both human and murine bladder cancer cells. Concurrently, KDM6A loss alters tumor metabolism, suppressing glycolysis and lactate production, which in turn diminishes histone lactylation (H3K9la, H3K18la) in regulatory T cells (Tregs). This leads to decreased expression of key immune-suppressive genes, including Foxp3, Tgfb, and Pdcd1. Consequently, reduced expansion of PD-1hi Tregs enhances the cytotoxic T cell-to-Treg ratio, improving the response to anti-PD-1 therapy in Kdm6a-deficient tumor-bearing mice. Collectively, these findings establish KDM6A as a key epigenetic regulator of genomic integrity and the immunosuppressive tumor microenvironment and provide a mechanistic rationale for utilizing KDM6A mutation status as a predictive biomarker to guide personalized treatment strategies in advanced bladder cancer.
2025-12-04 | PXD065234 | Pride
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: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
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:Given the heterogeneity of disease evident from study of the presentation, histomorphology, disease course, and molecular lesions of bladder cancer, a cohort of 8 non-muscle invasive and 11 muscle invasive bladder cancers were profiled for gene expression using the Affymetrix HG-U133A platform. Under an IRB-approved protocol, snap frozen tissues for 19 cases of bladder cancer were procured and profiled for gene expression using Affymetrix HG-U133A microarrays.
2012-12-24 | E-GEOD-37317 | biostudies-arrayexpress
Project description:Massive parallel sequencing projects identified KDM6A as a tumor suppressor gene with recurrent loss-of-function mutations multiple cancers. However, in breast cancer, reports on the functional role of KDM6A is paradoxical or even puzzling, suggesting the role of KDM6A may be context dependent. We sought to investigate the functional role of KDM6A in triple negative breast cancer with using MCF10A cells.
2022-05-23 | GSE131701 | GEO
Project description:Given the heterogeneity of disease evident from study of the presentation, histomorphology, disease course, and molecular lesions of bladder cancer, a cohort of 8 non-muscle invasive and 11 muscle invasive bladder cancers were profiled for gene expression using the Affymetrix HG-U133A platform.
2012-12-24 | GSE37317 | GEO
Project description:Although the intravesical instillation of Bacillus Calmette-Guerin (BCG) is widely used as adjuvant treatment for nonmuscle-invasive bladder cancers, the clinical benefit is variable across patients, and the molecular mechanisms underlying the sensitivity to BCG administration and disease progression are poorly understood. To establish the molecular signatures that predict the responsiveness and disease progression of bladder cancers treated with BCG, we performed transcriptome sequencing (RNA-seq) for 13 treatment-naïve and 22 post-treatment specimens obtained from 14 bladder cancer patients. To overcome disease heterogeneity, we used non-negative matrix factorization to identify the latent molecular features associated with drug responsiveness and disease progression. At least 12 molecular features were present, among which the immune-related feature was associated with drug responsiveness, indicating that pre-treatment anti-cancer immunity might dictate BCG responsiveness. We also identified disease progression-associated molecular features indicative of elevated cellular proliferation in post-treatment specimens. The progression-associated molecular features were validated in an extended cohort of BCG-treated bladder cancers. Our study advances understanding of the molecular mechanisms of BCG activity in bladder cancers and provides clinically relevant gene markers for evaluating and monitoring patients.
2023-12-25 | GSE244895 | GEO
Project description:Large-scale genome sequencing efforts of human tumors identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumor development and progression is largely unknown. Here, we identify the histone demethylase KDM6A as an important tumor suppressor in solid cancers, such as liver cancer and pancreatic cancer. KDM6A-deficient tumors show hyperactivation of mTORC1 signaling, whereas endogenous KDM6A re-expression in established KDM6A-deficient tumors diminishes mTORC1 activity by fostering the expression of crucial negative pathway regulators, such as DEPTOR, TSC1, and TSC2, resulting in tumor regression. Importantly, KDM6A expression in human tumors correlates with mTORC1 activity and KDM6A-deficient tumors exhibit increased sensitivity to mTORC1 inhibition. Hence, our results link KDM6A-dependent epigenetic remodeling to mTORC1 signaling and provide a potential therapeutic strategy for KDM6A-deficient tumors.
2022-07-20 | GSE155630 | GEO