Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Cells ; 12(6)2023 03 08.
Article in English | MEDLINE | ID: mdl-36980177

ABSTRACT

Epigenetic deregulation is a critical theme which needs further investigation in bladder cancer research. One of the most highly mutated genes in bladder cancer is KDM6A, which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of KDM6A in normal versus tumor settings, we identified the genomic landscape of KDM6A in normal, immortalized, and cancerous bladder cells. Our results showed differential KDM6A occupancy in 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 HES1 to be enriched at KDM6A peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in KDM6A and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed TLE co-repressors and HES1 as potential truncated and wild-type KDM6A interactors. With the aid of structural modeling, we explored how truncated KDM6A could interact with TLE and HES1, as well as RUNX and HHEX transcription factors. These structures provide a solid means of studying the functions of KDM6A independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer.


Subject(s)
Histone Demethylases , Urinary Bladder Neoplasms , Urinary Bladder , Humans , Cell Line , Gene Expression Regulation , Histone Demethylases/genetics , Histone Demethylases/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathology
2.
Commun Biol ; 6(1): 199, 2023 02 20.
Article in English | MEDLINE | ID: mdl-36805539

ABSTRACT

Bladder cancer is mostly present in the form of urothelium carcinoma, causing over 150,000 deaths each year. Its histopathological classification as muscle invasive (MIBC) and non-muscle invasive (NMIBC) is the most prominent aspect, affecting the prognosis and progression of this disease. In this study, we defined the active regulatory landscape of MIBC and NMIBC cell lines using H3K27ac ChIP-seq and used an integrative approach to combine our findings with existing data. Our analysis revealed FRA1 and FLI1 as two critical transcription factors differentially regulating MIBC regulatory landscape. We show that FRA1 and FLI1 regulate the genes involved in epithelial cell migration and cell junction organization. Knock-down of FRA1 and FLI1 in MIBC revealed the downregulation of several EMT-related genes such as MAP4K4 and FLOT1. Further, ChIP-SICAP performed for FRA1 and FLI1 enabled us to infer chromatin binding partners of these transcription factors and link this information with their target genes. Finally, we show that knock-down of FRA1 and FLI1 result in significant reduction of invasion capacity of MIBC cells towards muscle microenvironment using IC-CHIP assays. Our results collectively highlight the role of these transcription factors in selection and design of targeted options for treatment of MIBC.


Subject(s)
Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Muscles , Cell Line , Cell Movement/genetics , Chromatin Immunoprecipitation , Tumor Microenvironment , Protein Serine-Threonine Kinases , Intracellular Signaling Peptides and Proteins
3.
Turk J Biol ; 45(6): 656-666, 2021.
Article in English | MEDLINE | ID: mdl-35068946

ABSTRACT

Bladder cancer is one of the most frequent cancers and causes more than 150.000 deaths each year. During the last decade, several studies provided important aspects about genomic characterization, consensus subgroup definition, and transcriptional regulation of bladder cancer. Still, much more research needs to be done to characterize molecular signatures of this cancer in depth. At this point, the use of bladder cancer cell lines is quite useful for the identification and test of new signatures. In this study, we classified the bladder cancer cell lines according to the activities of regulons implicated in the regulation of primary bladder tumors. Our regulon gene expression-based classification revealed three groups, neuronal-basal (NB), luminal-papillary (LP), and basal-squamous (BS). These regulon gene expression-based classifications showed a quite good concordance with the consensus subgroups assigned by the primary bladder cancer classifier. Importantly, we identified FGFR1 regulon to be involved in the characterization of the NB group, where neuroendocrine signature genes were significantly upregulated, and further ß-catenin was shown to have significantly higher nuclear localization. LP groups were mainly driven by the regulons ERBB2, FOXA1, GATA3, and PPARG, and they showed upregulation of the genes involved in epithelial differentiation and urogenital development, while the activity of EGFR, FOXM1, STAT3, and HIF1A was implicated for the regulation of BS group. Collectively, our results and classifications may serve as an important guide for the selection and use of bladder cancer cell lines for experimental strategies, which aim to manipulate regulons critical for bladder cancer development.

4.
Sci Rep ; 10(1): 18667, 2020 10 29.
Article in English | MEDLINE | ID: mdl-33122695

ABSTRACT

Urothelial carcinoma of the bladder is the most frequent bladder cancer affecting more than 400,000 people each year. Histopathologically, it is mainly characterized as muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). Recently, the studies largely driven by consortiums such as TCGA identified the mutational landscape of both MIBC and NMIBC and determined the molecular subtypes of bladder cancer. Because of the exceptionally high rate of mutations in chromatin proteins, bladder cancer is thought to be a disease of chromatin, pointing out to the importance of studying epigenetic deregulation and the regulatory landscape of this cancer. In this study, we have analyzed ATAC-seq data generated for MIBC and integrated our findings with gene expression and DNA methylation data to identify subgroup specific regulatory patterns for MIBC. Our computational analysis revealed three MIBC regulatory clusters, which we named as neuronal, non-neuronal and luminal outlier. We have identified target genes of neuronal regulatory elements to be involved in WNT signaling, while target genes of non-neuronal and luminal outlier regulatory regions were enriched in epithelial differentiation and drug metabolism, respectively. Neuronal regulatory elements were determined to be ß-catenin targets (p value = 3.59e-08) consisting of genes involved in neurogenesis such as FGF9, and PROX1, and significantly enriched for TCF/LEF binding sites (p value = 1e-584). Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal (odds ratio = 31.33, p value = 1.786e-05). Our results for the first time identify regulatory elements characterizing neuronal bladder cancer and links these neuronal regulatory elements with WNT signaling via mutations in ß-catenin and its destruction complex components.


Subject(s)
Chromatin/metabolism , Neurons/metabolism , Urinary Bladder Neoplasms/metabolism , Wnt Signaling Pathway , beta Catenin/genetics , Humans , Regulatory Sequences, Nucleic Acid , Transcription Factors/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...