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Cancers 2019, 11(4), 481; https://doi.org/10.3390/cancers11040481

Contingencies of UTX/KDM6A Action in Urothelial Carcinoma

1
Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
2
Department of Otolaryngology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
3
Biological and Medical Research Centre (BMFZ), Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
4
Chair for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Received: 28 February 2019 / Revised: 28 March 2019 / Accepted: 2 April 2019 / Published: 4 April 2019
(This article belongs to the Collection Histone Modification in Cancer)
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Abstract

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 KDM6A 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.
Keywords: bladder cancer; chromatin regulator; histone demethylase; histone methylation; COMPASS complex; RNA-sequencing; nuclear localization; UTX; MLL bladder cancer; chromatin regulator; histone demethylase; histone methylation; COMPASS complex; RNA-sequencing; nuclear localization; UTX; MLL
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Lang, A.; Yilmaz, M.; Hader, C.; Murday, S.; Kunz, X.; Wagner, N.; Wiek, C.; Petzsch, P.; Köhrer, K.; Koch, J.; Hoffmann, M.J.; Greife, A.; Schulz, W.A. Contingencies of UTX/KDM6A Action in Urothelial Carcinoma. Cancers 2019, 11, 481.

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