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Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer

ABSTRACT: Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer

PROVIDER: PRJNA660040 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12541938.fastq.gz	Fastqsanger.gz
	SRR12541939.fastq.gz	Fastqsanger.gz
	SRR12541940.fastq.gz	Fastqsanger.gz
	SRR12541941.fastq.gz	Fastqsanger.gz
	SRR12541942.fastq.gz	Fastqsanger.gz

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Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [RNA-seq]

Project description:Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most differentiated luminal tumors to the more aggressive and least differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly co-occur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.

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Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [ChIP-seq]

2020-09-15 | GSE157090 | GEO

Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [ChIP-seq]

Project description:Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [ChIP-seq]

| PRJNA660044 | ENA

Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [RNA-seq]

Project description:Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [RNA-seq]

| PRJNA660043 | ENA

Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

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

FGFR3-shRNA induced transcriptional changes in RT112 bladder cancer cells

Project description:Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. In this study with a bladder carcinoma cell line expressing inducible FGFR3 shRNAs, we sought to identiy transcriptional targets of FGFR3 and investigate their contribution to bladder cancer development. Bladder cancer cell line RT112 was transduced with a doxycycline-inducible control EGFP shRNA or three independent FGFR3 shRNAs, designated FGFR3 shRNA 2-4, FGFR3 shRNA 4-1 and FGFR3 shRNA 6-16. These four cell lines were treated with or without doxycycline for 48 hr to deplete FGFR3 protein prior to the isolation of mRNA for microarray analysis. Genes that were differentially expressed after doxycycline induction in all three FGFR3-depleted cell lines but not in the control cell line were considered potential FGFR3-regulated genes. Each treatment group was run in triplcates, and there are 24 samples.

2012-11-07 | E-GEOD-41035 | biostudies-arrayexpress

Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene-expression programs in bladder cancer.

Project description:Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most-differentiated luminal tumors to the more aggressive and least-differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly cooccur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.

| S-EPMC7568298 | biostudies-literature

Transcriptome analysis for KDM6A mutated urothelial bladder carcinoma and EZH2 inhibitor treated KDM6A mutated urothelial bladder carcinoma

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.

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FGFR3-shRNA induced transcriptional changes in RT112 bladder cancer cells

2012-11-07 | GSE41035 | GEO

Gene expression data from FGFR3 induced mouse bladder tumors

Project description:Somatic mutations of the fibroblast growth factor receptor 3 (FGFR3) are one of the most frequent genetic alterations in bladder carcinomas. We report here that human-FGFR3-S249C expression in urothelial cells of transgenic mice induces low-grade papillary tumors presenting genomic instability and resembling human pTa urothelial tumors at the transcriptomic level. Mutated-FGFR3 expression levels impacted the incidence of tumor formation and could account for the tissue specificity of human mutated FGFR3-driven tumors restricted to epithelia presenting high normal expression levels of FGFR3.

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