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.
Highlights
The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX, known as Lysine demethylase 6A, gene name KDM6A) demethylates K27me2/3 on histone3 (H3), which is usually associated with gene activation [1]
Mutations of the epigenetic regulator UTX/KDM6A occur at a similar frequency as those in p53 in urothelial carcinoma, their consequences are poorly understood
We show that introduction of functional UTX/KDM6A has quite diverse effects in urothelial carcinoma cell lines representing a broad spectrum of genotypes and phenotypes that reflect the heterogeneity of this cancer type
Summary
The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX, known as Lysine demethylase 6A, gene name KDM6A) demethylates K27me2/3 on histone3 (H3), which is usually associated with gene activation [1]. The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX, known as Lysine demethylase 6A, gene name KDM6A) demethylates K27me2/3 on histone. In most instances UTX acts in conjunction with the COMPASS complex [2]. This complex, which mediates H3K4 methylation, comprises a core complex termed WRAD (WDR5, RBBP5, ASH2L and DPY30) and the MLL3 (KMT2C) or MLL2/4. In estrogen receptor-dependent breast cancer UTX serves as a coactivator that facilitates gene activation by the estrogen-receptor α and its co-transcription factors [5]. UTX function is compromised or abolished by deleterious mutations
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