Epigenetic drug library screening reveals targeting DOT1L abrogates NAD<sup>+</sup> synthesis by reprogramming H3K79 methylation in uveal melanoma

Xiang Gu; Yu Hua; Jie Yu; Ludi Yang; Shengfang Ge; Renbing Jia; Peiwei Chai; Ai Zhuang; Xianqun Fan

doi:10.1016/j.jpha.2022.11.008

Volume 13 Issue 1

Jan. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(1): 24-38

Xiang Gu, Yu Hua, Jie Yu, Ludi Yang, Shengfang Ge, Renbing Jia, Peiwei Chai, Ai Zhuang, Xianqun Fan. Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 24-38. doi: 10.1016/j.jpha.2022.11.008

Citation:

Xiang Gu, Yu Hua, Jie Yu, Ludi Yang, Shengfang Ge, Renbing Jia, Peiwei Chai, Ai Zhuang, Xianqun Fan. Epigenetic drug library screening reveals targeting DOT1L abrogates NAD⁺ synthesis by reprogramming H3K79 methylation in uveal melanoma[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 24-38. doi: 10.1016/j.jpha.2022.11.008

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

doi: 10.1016/j.jpha.2022.11.008

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

Funds:

This work was supported by grants from Shanghai Key Clinical Specialty, Shanghai Eye Disease Research Center (Grant No.: 2022ZZ01003 to Xianqun Fan), the National Key Research and Development Plan (Grant No.: 2018YFC1106100 to Xianqun Fan), the National Natural Science Foundation of China (Grant Nos.: 12275178 to Shengfang Ge and 82103240 to Peiwei Chai), Innovative Research Team of High-level Local Universities in Shanghai (Grant Nos.: SHSMU- ZDCX20210902 to Renbing Jia and SHSMU-ZDCX20210900 to Xianqun Fan), the Science and Technology Commission of Shanghai (Grant No.: 19JC1410200 to Xianqun Fan), and Cross-disciplinary Research Fund of Shanghai Ninth People's Hospital, Shanghai Jiao Tong university School of Medicine (Grant No.: JYJC202210 to Ai Zhuang).

Received Date: Jul. 15, 2022
Accepted Date: Nov. 22, 2022
Rev Recd Date: Nov. 16, 2022
Publish Date: Nov. 28, 2022

Abstract

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 Cleavage Under Targets and Tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and bioinformatics analysis, we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase (NAPRT) and epigenetically activated its expression. Importantly, NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide (NAD⁺) synthesis. Therapeutically, DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79 (H3K79me2) in the NAPRT promoter, thereby inhibiting the malignant behaviors of UM. Conclusively, our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.
- Histone methylation,
- Metabolic reprogramming,
- Uveal melanoma,
- Transcriptional addiction

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