Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines

Abstract

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 KDM6A, which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of KDM6A in normal versus tumor settings, we identified the genomic landscape of KDM6A in normal, immortalized, and cancerous bladder cells. Our results showed differential KDM6A occupancy in the genes involved in cell differentiation, chromatin organization, and Notch signaling depending on the cell type and the mutation status of KDM6A. Transcription factor motif analysis revealed HES1 to be enriched at KDM6A peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in KDM6A and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed TLE co-repressors and HES1 as potential truncated and wild-type KDM6A interactors. With the aid of structural modeling, we explored how truncated KDM6A could interact with TLE and HES1, as well as RUNX and HHEX transcription factors. These structures provide a solid means of studying the functions of KDM6A independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer.

Circ_0000235 targets MCT4 to promote glycolysis and progression of bladder cancer by sponging miR-330-5p

“…About 524,000 Bca cases were diagnosed and 229,000 Bca-related deaths were recorded in 2019 [ 2 ]. The majority of Bca patients suffer from non-muscle invasive bladder cancer (NMIBC), while the remainder suffer from muscle invasive bladder cancer (MIBC) or metastatic Bca [ 3 , 4 ]. Cisplatin-based combination therapy has been the primary treatment option for MIBC and metastatic Bca for approximately 20 years.…”