Consequences and therapeutic vulnerabilities of KDM6A and KDM6C mutations in urothelial carcinoma

Bladder cancers are approximately four times as likely to arise in men than in women. A series of recent studies have indicated that this difference may result in part from genes that are encoded on the X and Y chromosomes. This project aims to understand the functions of the X-chromosome KDM6A (also known as UTX) tumor suppressor gene and the closely related Y-chromosome KDM6C (also known as UTY) gene in bladder carcinogenesis. We will i) identify at the genomic level the effects of their loss of function on gene transcription and histone modifications, ii) characterise the transient and stable interactomes of KDM6A and KDM6C to biochemically define the protein complexes that they function in, and iii) screen for genetic and pharmaceutical vulnerabilities imposed on bladder cancer cells by mutations in KDM6A and/or KDM6C. We will study both male and female normal urothelial and urothelial carcinoma cells to investigate similarities and differences in the functions of KDM6A and KDM6C. Close interactions with other UcarE projects will allow the further investigation of findings made in our human cell line studies in mouse bladder cancer models and engineered organoids, human urothelial carcinoma organoids and in pathological samples of human bladder cancers at different stages of development. Collectively, our proposed research program aims to comprehensively characterize the molecular and biochemical functions of the KDM6A/KDM6C pair of tumor suppressor genes and to develop targeted therapies for tumors harboring these mutations.