Lang Alexander, Yilmaz Merve, Hader Christiane, Murday Sammy, Kunz Xenia, Wagner Nicholas, Wiek Constanze, Petzsch Patrick, Köhrer Karl, Koch Julian, Hoffmann Michéle J, Greife Annemarie, Schulz Wolfgang A
Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
Department of Otolaryngology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Cancers (Basel). 2019 Apr 4;11(4):481. doi: 10.3390/cancers11040481.
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 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.
组蛋白去甲基化酶X连锁泛转录四肽重复蛋白（UTX/KDM6A）可使基因和增强子处的H3K27me2/3去甲基化，在尿路上皮癌（UC）中常因突变而失活。然而，其失活的后果却知之甚少。我们研究了在一系列UC细胞系中适度过表达UTX的后果，这些细胞系有或没有UTX及其相互作用伙伴的突变，还有一个正常对照细胞系。对细胞增殖的影响，尤其是长期影响，在不同细胞系之间差异很大，从有害到有益不等。同样，通过RNA测序确定的对整体基因表达的影响也各不相同，不同细胞系之间上调或下调的基因很少有重叠。我们的数据表明，UTX在UC中并非以统一方式发挥作用。相反，其作用取决于多种偶然因素，其中最主要是的是与UTX在COMPASS复合物中相互作用的KMT2C和KMT2D的状态。特别是，我们提供的证据表明，这些因素决定了细胞核中UTX的含量。
