Contingencies of UTX/KDM6A Action in Urothelial Carcinoma

Lang, Alexander; Yılmaz, Merve; Hader, Christiane; Murday, Sammy; Kunz, Xenia; Wagner, Nicholas; Wiek, Constanze; Petzsch, Patrick; Köhrer, Karl; Koch, Julian; Hoffmann, Michèle J.; Greife, Annemarie; Schulz, Wolfgang A.

doi:10.3390/cancers11040481

Cited by 27 publications

(29 citation statements)

References 35 publications

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“…GSEA of Kyoto Encyclopedia of Genes and Genomes pathways between gene sets of BC samples with mutated and wild-type KDM6A demonstrated that the signalling pathways of cell-adhesion molecules, ECM receptor interaction, and focal adhesion were also suppressed by KDM6A mutation. These ndings support the need for further in-depth study of the possible role of KDM6A in regulation of cell adhesion and morphology in BC [21]. KDM6A de ciency has been suggested to activate pathways of chemokines and cytokines, increase M2 macrophage polarization, increase cancer stem cell abundance, and act synergistically with p53 haploinsu ciency [22].…”

Section: Discussionsupporting

confidence: 55%

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Chen

Lin

Pang

et al. 2020

Preprint

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Background: Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response. Methods: We mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC. Results: We found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency of KDM6A mutations in the TCGA and ICGC datasets was 25.97% and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating lymphocytes and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A expression level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response. Conclusion: Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response. Key Words: KDM6A, bladder cancer, mutation, immune

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Section: Discussionsupporting

confidence: 55%

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Chen

Lin

Pang

et al. 2020

Preprint

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“…However demethylation by KDM6A appears necessary for tumor maintenance through activation of the NOTCH pathway [61]. The impact of KDM6A varied between urothelial carcinoma cell lines, dependent in part on the status of KMT2C and KMT2D [62]. The paradoxical roles of KDM6A in both suppressing and supporting oncogenesis have been reviewed recently [20,63].…”

Section: Kdm6a In Developmentmentioning

confidence: 99%

Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation

Gažová

Lengeling

Summers

2019

Molecular Genetics and Metabolism

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Histone demethylases remove transcriptional repressive marks from histones in the nucleus. KDM6A (also known as UTX) is a lysine demethylase which acts on the trimethylated lysine at position 27 in histone 3. The KDM6A gene is located on the X chromosome but escapes X inactivation even though it is not located in the pseudoautosomal region. There is a homologue of KDM6A on the Y chromosome, known as UTY. UTY was thought to have lost its demethylase activity and to represent a non-functional remnant of the ancestral KDM6A gene. However, results with knockout mice suggest that the gene is expressed and the protein performs some function within the cell. Female mice with homozygous deletion of Kdm6a do not survive, but hemizygous males are viable, attributed to the presence of the Uty gene. KDM6A is mutated in the human condition Kabuki syndrome type 2 (OMIM 300867) and in many cases of cancer. The amino acid sequence of KDM6A has been conserved across animal phyla, although it is only found on the X chromosome in eutherian mammals. In this review, we reanalyse existing data from various sources (protein sequence comparison, evolutionary genetics, transcription factor binding and gene expression analysis) to determine the function, expression and evolution of KDM6A and UTY and show that UTY has a functional role similar to KDM6A in metabolism and development.

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“…In the T-24 cell line with a homozygous truncating KDM6A mutation, a weak band at approximately 100 kDa may correspond to the expected truncated protein. Following CRISPR/Cas-mediated KDM6A knockout in the SW1710 cell line (as described in [21]) UTX protein became undetectable ( Figure S1b). Treatment of HBLAK cells with siRNA directed against KDM6A/UTX mRNA (siRNA 01) substantially decreased mRNA levels and almost completely obliterated protein expression after 2 d ( Figure S1c,d).…”

Section: Efficiency Of Utx Knockdownmentioning

confidence: 97%

“…Culture and use of normal urothelial cells from ureters of patients undergoing nephrectomy was permitted by the ethical committee of the HHU medical faculty (#1788). UC cell lines were cultured in Dulbecco's modified eagle's medium (DMEM, ThermoFisher Scientific, Langenselbold, Germany) supplemented with 10% fetal calf serum as previously described [21]. Passaging was performed using trypsin (Sigma Aldrich, Munich).…”

Section: Cell Culturementioning

confidence: 99%

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Knockdown of UTX/KDM6A Enriches Precursor Cell Populations in Urothelial Cell Cultures and Cell Lines

Lang

Whongsiri

Yılmaz

et al. 2020

Cancers

Self Cite

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The histone demethylase UTX (gene: KDM6A) directs cell and tissue differentiation during development. Deleterious mutations in KDM6A occur in many human cancers, most frequently in urothelial carcinoma. The consequences of these mutations are poorly understood; plausibly, they may disturb urothelial differentiation. We therefore investigated the effects of UTX siRNA-mediated knockdown in two in vitro models of urothelial differentiation; namely, primary cultures of urothelial epithelial cells treated with troglitazone and PD153035 and the immortalized urothelial cell line HBLAK treated with high calcium and serum. In both models, efficient UTX knockdown did not block morphological and biochemical differentiation. An apparent delay was due to a cytotoxic effect on the cell cultures before the initiation of differentiation, which induced apoptosis partly in a p53-dependent manner. As a consequence, slowly cycling, smaller, KRT14 high precursor cells in the HBLAK cell line were enriched at the expense of more differentiated, larger, proliferating KRT14 low cells. UTX knockdown induced apoptosis and enriched KRT14 high cells in the BFTC-905 papillary urothelial carcinoma cell line as well. Our findings suggest an explanation for the frequent occurrence of KDM6A mutations across all stages and molecular subtypes of urothelial carcinoma, whereby loss of UTX function does not primarily impede later stages of urothelial differentiation, but favors the expansion of precursor populations to provide a reservoir of potential tumor-initiating cells.

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Contingencies of UTX/KDM6A Action in Urothelial Carcinoma

Cited by 27 publications

References 35 publications

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation

Knockdown of UTX/KDM6A Enriches Precursor Cell Populations in Urothelial Cell Cultures and Cell Lines

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