Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines

• Published in: Cells (Basel, Switzerland) Switzerland), 2023-03, Vol.12 (6), p.836
• Main Authors: Özden-Yılmaz, Gülden, Savas, Busra, Bursalı, Ahmet, Eray, Aleyna, Arıbaş, Alirıza, Senturk, Serif, Karaca, Ezgi, Karakülah, Gökhan, Erkek-Ozhan, Serap
• Format: Article
• Language: English
• Subjects: Antibodies; Bladder cancer; Cancer; Cell differentiation; Cell Line; Chromatin; chromatin regulation; Development and progression; DNA methylation; Epigenetic inheritance; Epigenetics; Experiments; Gene Expression Regulation; Genes; Genetic aspects; Genetic regulation; Health aspects; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; Immunoprecipitation; KDM6A; Mutation; protein–protein interactions; Repressors; structural modeling; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumorigenesis; Urinary Bladder - pathology; Urinary Bladder Neoplasms - pathology
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12060836

Epigenetic deregulation is a critical theme which needs further investigation in bladder cancer research. One of the most highly mutated genes in bladder cancer is , which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of in normal versus tumor settings, we identified the genomic landscape of in normal, immortalized, and cancerous bladder cells. Our results showed differential occupancy in the genes involved in cell differentiation, chromatin organization, and Notch signaling depending on the cell type and the mutation status of . Transcription factor motif analysis revealed to be enriched at peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed co-repressors and as potential truncated and wild-type interactors. With the aid of structural modeling, we explored how truncated could interact with and , as well as and transcription factors. These structures provide a solid means of studying the functions of independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of malfunction in bladder cancer.