Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy
文献类型：期刊论文
| 作者 | Bai, Wenjing6,7,8; Xu, Jinxin6,7; Gu, Wenbin6,7,8; Wang, Danyang6; Cui, Ying5; Rong, Weidong6,7,8; Du, Xiaoan4,6,7; Li, Xiaoxia4,6; Xia, Cuicui6,7,8; Gan, Qingqing6,7 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2025-01-08 |
| 卷号 | 16期号:1页码:22 |
| DOI | 10.1038/s41467-024-55481-7 |
| 英文摘要 | UHRF1 maintains DNA methylation by recruiting DNA methyltransferases to chromatin. In mouse, these dynamics are potently antagonized by a natural UHRF1 inhibitory protein STELLA, while the comparable effects of its human ortholog are insufficiently characterized, especially in cancer cells. Herein, we demonstrate that human STELLA (hSTELLA) is inadequate, while mouse STELLA (mSTELLA) is fully proficient in inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. Structural studies reveal a region of low sequence homology between these STELLA orthologs that allows mSTELLA but not hSTELLA to bind tightly and cooperatively to the essential histone-binding, linked tandem Tudor domain and plant homeodomain (TTD-PHD) of UHRF1, thus mediating ortholog-specific UHRF1 inhibition. For translating these findings to cancer therapy, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach in which the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA hypermethylation and impair colorectal cancer tumorigenicity. |
| WOS关键词 | DNA METHYLATION PATTERNS ; EPIGENETIC INHERITANCE ; CHROMATIN-STRUCTURE ; TANDEM TUDOR ; STEM-CELLS ; GENES ; PHD ; HYPERMETHYLATION ; DEMETHYLATION ; RECOGNITION |
| 资助项目 | U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)[22107101] ; National Natural Science Foundation of China[R01ES011858] ; National Institute of Environmental Health Sciences ; Samuel Waxman Research Foundation ; Hodson Trust[2022YFA1303100] ; Hodson Trust[2023YFF0724200] ; National Key R&D Program of China[2021B1515420002] ; National Key R&D Program of China[2023B1212060050] ; Guangdong Basic and Applied Basic Research Foundation[2024A04J4358] ; Science and Technology Projects in Guangzhou[2021QN02Y734] ; Pearl River Talents Plan[SKLRD-OP-202213] ; Pearl River Talents Plan[LG-QS-202205-07] ; Open Project of State Key Laboratory of Respiratory Disease[GIBHBRP23-03] ; Open Project of State Key Laboratory of Respiratory Disease[GIBHBRP24-03] ; Basic Research Project of Guangzhou Institutes of Biomedicine and Health[R01CA283463] ; National Cancer Institute, National Institutes of Health |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001398317800004 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315902]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Liu, Jinsong; Baylin, Stephen B.; Kong, Xiangqian |
| 作者单位 | 1.Guizhou Med Univ, Sch Pharm, Guiyang 550004, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Van Andel Inst, Dept Epigenet, Grand Rapids, MI 49503 USA 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sch Med, Baltimore, MD 21287 USA 6.Chinese Acad Sci, Inst Drug Discovery, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Peoples R China 7.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou 510530, Peoples R China 8.Chinese Acad Sci, Guangdong Prov Key Lab Stem Cell & Regenerat Med, China New Zealand Joint Lab Biomed & Hlth, Guangzhou Inst Biomed & Hlth,CAS Key Lab Regenerat, Guangzhou 510530, Peoples R China |
| 推荐引用方式 GB/T 7714 | Bai, Wenjing,Xu, Jinxin,Gu, Wenbin,et al. Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy[J]. NATURE COMMUNICATIONS,2025,16(1):22. |
| APA | Bai, Wenjing.,Xu, Jinxin.,Gu, Wenbin.,Wang, Danyang.,Cui, Ying.,...&Kong, Xiangqian.(2025).Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy.NATURE COMMUNICATIONS,16(1),22. |
| MLA | Bai, Wenjing,et al."Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy".NATURE COMMUNICATIONS 16.1(2025):22. |
入库方式： OAI收割
来源：上海药物研究所
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