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Abstract

Bladder neoplasms are classified into non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). While NMIBC is a low-grade tumor, MIBC is a high-grade tumor that tends to metastasize. MIBC tumors are further grouped into different molecular subtypes defined by specific gene expression signatures. Among these, luminal tumors are characterized by high expression of GATA3, FOXA1, and PPARG. PPARG is required for the normal differentiation of the urothelium and is one of the vital drivers of luminal MIBC. High PPARG expression is a key feature of luminal MIBC, however, the mechanisms of PPARG regulation are unclear and need further examination to understand lineage commitment and enable new therapeutic strategies. To understand regulation of PPARG, we previously conducted a whole-genome knockout CRISPR screen that revealed potential regulators of PPARG and other luminal genes. Disruptor of telomeric silencing 1-like enzyme (DOT1L), a lysine histone methyltransferase, was one of the top ranked candidates in the screen. Here, we report that DOT1L is an epigenetic regulator of PPARG, FOXA1, and GATA3. We show that DOT1L mediated H3K79me2 is required for PPARG, FOXA1, and GATA3 expression and for maintaining the luminal phenotype in MIBC. Inhibition of DOT1L activity in luminal MIBC cells decreases PPARG, FOXA1, and GATA3 expression, resulting in loss of luminal gene expression signature and a shift towards basal-like phenotype. Combined, my work identifies an epigenetic mechanism of sub-type regulation in MIBC that can be attenuated by DOT1L inhibitors.