Contingencies of UTX/KDM6A Action in Urothelial Carcinoma
The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX/KDM6A) demethylates H3K27me2/3 at genes and enhancers and is often inactivated by mutations in urothelial carcinoma (UC). The consequences of its inactivation are however poorly understood. We have invest...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/4/481 |
| _version_ | 1797722433656979456 |
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| author | Alexander Lang Merve Yilmaz Christiane Hader Sammy Murday Xenia Kunz Nicholas Wagner Constanze Wiek Patrick Petzsch Karl Köhrer Julian Koch Michéle J. Hoffmann Annemarie Greife Wolfgang A. Schulz |
| author_facet | Alexander Lang Merve Yilmaz Christiane Hader Sammy Murday Xenia Kunz Nicholas Wagner Constanze Wiek Patrick Petzsch Karl Köhrer Julian Koch Michéle J. Hoffmann Annemarie Greife Wolfgang A. Schulz |
| author_sort | Alexander Lang |
| collection | DOAJ |
| description | The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX/KDM6A) demethylates H3K27me2/3 at genes and enhancers and is often inactivated by mutations in urothelial carcinoma (UC). The consequences of its inactivation are however poorly understood. We have investigated the consequences of moderate UTX overexpression across a range of UC cell lines with or without mutations in <i>KDM6A</i> or its interaction partners and in a normal control cell line. Effects on cell proliferation, especially long-term, varied dramatically between the cell lines, ranging from deleterious to beneficial. Similarly, effects on global gene expression determined by RNA-Seq were variable with few overlapping up- or downregulated genes between the cell lines. Our data indicate that UTX does not act in a uniform fashion in UC. Rather, its effect depends on several contingencies including, prominently, the status of KMT2C and KMT2D which interact with UTX in the COMPASS complex. In particular, we provide evidence that these factors determine the amount of nuclear UTX. |
| first_indexed | 2024-03-12T09:47:15Z |
| format | Article |
| id | doaj.art-8c5fdebc0cfd4f33b49a4011c816d997 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:47:15Z |
| publishDate | 2019-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8c5fdebc0cfd4f33b49a4011c816d9972023-09-02T12:47:52ZengMDPI AGCancers2072-66942019-04-0111448110.3390/cancers11040481cancers11040481Contingencies of UTX/KDM6A Action in Urothelial CarcinomaAlexander Lang0Merve Yilmaz1Christiane Hader2Sammy Murday3Xenia Kunz4Nicholas Wagner5Constanze Wiek6Patrick Petzsch7Karl Köhrer8Julian Koch9Michéle J. Hoffmann10Annemarie Greife11Wolfgang A. Schulz12Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyDepartment of Otolaryngology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyBiological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyBiological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyChair for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyChair for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyThe histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX/KDM6A) demethylates H3K27me2/3 at genes and enhancers and is often inactivated by mutations in urothelial carcinoma (UC). The consequences of its inactivation are however poorly understood. We have investigated the consequences of moderate UTX overexpression across a range of UC cell lines with or without mutations in <i>KDM6A</i> or its interaction partners and in a normal control cell line. Effects on cell proliferation, especially long-term, varied dramatically between the cell lines, ranging from deleterious to beneficial. Similarly, effects on global gene expression determined by RNA-Seq were variable with few overlapping up- or downregulated genes between the cell lines. Our data indicate that UTX does not act in a uniform fashion in UC. Rather, its effect depends on several contingencies including, prominently, the status of KMT2C and KMT2D which interact with UTX in the COMPASS complex. In particular, we provide evidence that these factors determine the amount of nuclear UTX.https://www.mdpi.com/2072-6694/11/4/481bladder cancerchromatin regulatorhistone demethylasehistone methylationCOMPASS complexRNA-sequencingnuclear localizationUTXMLL |
| spellingShingle | Alexander Lang Merve Yilmaz Christiane Hader Sammy Murday Xenia Kunz Nicholas Wagner Constanze Wiek Patrick Petzsch Karl Köhrer Julian Koch Michéle J. Hoffmann Annemarie Greife Wolfgang A. Schulz Contingencies of UTX/KDM6A Action in Urothelial Carcinoma Cancers bladder cancer chromatin regulator histone demethylase histone methylation COMPASS complex RNA-sequencing nuclear localization UTX MLL |
| title | Contingencies of UTX/KDM6A Action in Urothelial Carcinoma |
| title_full | Contingencies of UTX/KDM6A Action in Urothelial Carcinoma |
| title_fullStr | Contingencies of UTX/KDM6A Action in Urothelial Carcinoma |
| title_full_unstemmed | Contingencies of UTX/KDM6A Action in Urothelial Carcinoma |
| title_short | Contingencies of UTX/KDM6A Action in Urothelial Carcinoma |
| title_sort | contingencies of utx kdm6a action in urothelial carcinoma |
| topic | bladder cancer chromatin regulator histone demethylase histone methylation COMPASS complex RNA-sequencing nuclear localization UTX MLL |
| url | https://www.mdpi.com/2072-6694/11/4/481 |
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