Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma
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 e...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Journal of Pharmaceutical Analysis |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2095177922001216 |
| _version_ | 1797938123381932032 |
|---|---|
| author | Xiang Gu Yu Hua Jie Yu Ludi Yang Shengfang Ge Renbing Jia Peiwei Chai Ai Zhuang Xianqun Fan |
| author_facet | Xiang Gu Yu Hua Jie Yu Ludi Yang Shengfang Ge Renbing Jia Peiwei Chai Ai Zhuang Xianqun Fan |
| author_sort | Xiang Gu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T18:54:47Z |
| format | Article |
| id | doaj.art-82109ba1196e4e51967cb62b7d179289 |
| institution | Directory Open Access Journal |
| issn | 2095-1779 |
| language | English |
| last_indexed | 2024-04-10T18:54:47Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmaceutical Analysis |
| spelling | doaj.art-82109ba1196e4e51967cb62b7d1792892023-02-01T04:25:43ZengElsevierJournal of Pharmaceutical Analysis2095-17792023-01-011312438Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanomaXiang Gu0Yu Hua1Jie Yu2Ludi Yang3Shengfang Ge4Renbing Jia5Peiwei Chai6Ai Zhuang7Xianqun Fan8Department 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaCorresponding author.; 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, ChinaCorresponding author.; 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, ChinaCorresponding author.; 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, ChinaUveal 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.http://www.sciencedirect.com/science/article/pii/S2095177922001216Histone methylationMetabolic reprogrammingUveal melanomaTranscriptional addiction |
| spellingShingle | 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 Journal of Pharmaceutical Analysis Histone methylation Metabolic reprogramming Uveal melanoma Transcriptional addiction |
| title | Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma |
| title_full | Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma |
| title_fullStr | Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma |
| title_full_unstemmed | Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma |
| title_short | Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma |
| title_sort | epigenetic drug library screening reveals targeting dot1l abrogates nad synthesis by reprogramming h3k79 methylation in uveal melanoma |
| topic | Histone methylation Metabolic reprogramming Uveal melanoma Transcriptional addiction |
| url | http://www.sciencedirect.com/science/article/pii/S2095177922001216 |
| work_keys_str_mv | AT xianggu epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT yuhua epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT jieyu epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT ludiyang epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT shengfangge epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT renbingjia epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT peiweichai epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT aizhuang epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma AT xianqunfan epigeneticdruglibraryscreeningrevealstargetingdot1labrogatesnadsynthesisbyreprogrammingh3k79methylationinuvealmelanoma |