Mesane tümör oluşumunda görev alan moleküler mekanizmaların deneysel ve hesaplamalı yaklaşımlar ile anlaşılması

It is known that genes involved in chromatin regulation are highly mutated in bladder cancer. For this reason, it is very important to understand the molecular mechanisms that play a role in the epigenetic regulation of bladder cancer and that may cause tumor formation. The primary goal in this thesis is to decipher the epigenetic mechanisms deregulated in bladder cancer using both experimental and computational methods. For this aim, first regulatory landscapes of bladder cancer molecular subtypes have been investigated using published data which showed active chromatin regions in bladder cancer using ATAC-seq. Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal. Secondly, we aimed to understand the epigenetic deregulation in bladder cancer via employing experimental techniques. For this purpose, we focused on KDM6A, which is among the top frequently mutated chromatin modifiers in bladder cancer. To investigate how KDM6A depletion affects phenotypic and epigenomic profile of bladder cancer, we knock-out KDM6A in a muscle invasive bladder cancer cell line, 5637. No significant viability changes between 5637 and KDM6A-null 5637 have been detected in long term growth of the cells. Genes marked with top H3K4me3 peaks were enriched for chromatin organization pathway, including the chromatin modifier, HDAC1. Our findings suggest that in the absence of KDM6A chromatin modifier, repressive chromatin states might be abundant, which will be further investigated in future.