GSE174167
Antitumor effects of DOT1L inhibition in retinoblastoma
Epigenetic dysregulation is one of the molecular mechanisms contributing to retinoblastoma (RB) development. Consistent with this notion, human RB tumors show an aberrant expression of many chromatin regulators whereas normal retina or nontumoral retinal tissues do not have any detectable expression of such proteins. Among the chromatin regulators found to be misregulated in RB, this study focuses on a histone methyltransferase DOT1L to assess the therapeutic potential of its targeting for RB treatment. We found that pharmacological inhibition of DOT1L has growth-inhibitory effects on RB cells by itself and also can sensitize RB cells to standard chemotherapeutic drugs by inducing more robust apoptotic cell death when cells are subjected to combination treatments. To understand the molecular mechanisms underlying the growth inhibition and chemosensitization of RB cells upon DOT1L inhibition, we performed the gene expression profiling in Y79 cells treated with a DOT1L inhibitor EPZ5676 in comparison with a vehicle control by RNA-sequencing to identify differentially expressed genes. Our RNA-seq results revealed that DOT1L inhibition downregulates several genes which are known to be misregulated in cancers, including HMGA2. Overall design: Gene expression profiling of Y79 retinoblastoma cell line treated with 10 µM EPZ5676 for 6 days in comparison with a vehicle control (DMSO); Identification of differentially expressed genes between the DMSO and EPZ5676 groups using three independent biological replicates