Epigenetic drug library screening reveals targeting DOT1L abrogates NAD⁺ synthesis by reprogramming H3K79 methylation in uveal melanoma.

ABSTRACT: Uveal melanoma (UM) is the most frequent and life-threatening ocular malignancy in adults. Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis. However, a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic. Herein, using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers, we observed that disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of histone H3 lysine 79 (H3K79), was activated in UM, especially in the high-risk group. Concordantly, a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells, both in vitro and in vivo. Combining C

SUBMITTER: Gu X 

PROVIDER: S-EPMC9937798 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature