Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy
Abstract 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....
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55481-7 |
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| author | Wenjing Bai Jinxin Xu Wenbin Gu Danyang Wang Ying Cui Weidong Rong Xiaoan Du Xiaoxia Li Cuicui Xia Qingqing Gan Guantao He Huahui Guo Jinfeng Deng Yuqiong Wu Ray-Whay Chiu Yen Srinivasan Yegnasubramanian Scott B. Rothbart Cheng Luo Linping Wu Jinsong Liu Stephen B. Baylin Xiangqian Kong |
| author_facet | Wenjing Bai Jinxin Xu Wenbin Gu Danyang Wang Ying Cui Weidong Rong Xiaoan Du Xiaoxia Li Cuicui Xia Qingqing Gan Guantao He Huahui Guo Jinfeng Deng Yuqiong Wu Ray-Whay Chiu Yen Srinivasan Yegnasubramanian Scott B. Rothbart Cheng Luo Linping Wu Jinsong Liu Stephen B. Baylin Xiangqian Kong |
| author_sort | Wenjing Bai |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-b19436831a664ed7abb041269b3bacd5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b19436831a664ed7abb041269b3bacd52025-01-12T12:31:03ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-024-55481-7Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapyWenjing Bai0Jinxin Xu1Wenbin Gu2Danyang Wang3Ying Cui4Weidong Rong5Xiaoan Du6Xiaoxia Li7Cuicui Xia8Qingqing Gan9Guantao He10Huahui Guo11Jinfeng Deng12Yuqiong Wu13Ray-Whay Chiu Yen14Srinivasan Yegnasubramanian15Scott B. Rothbart16Cheng Luo17Linping Wu18Jinsong Liu19Stephen B. Baylin20Xiangqian Kong21Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesState Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesInstitute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of MedicineGuangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesState Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesInstitute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesState Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesInstitute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesInstitute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesInstitute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of MedicineDepartment of Epigenetics, Van Andel InstituteState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesInstitute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesState Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of MedicineGuangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41467-024-55481-7 |
| spellingShingle | Wenjing Bai Jinxin Xu Wenbin Gu Danyang Wang Ying Cui Weidong Rong Xiaoan Du Xiaoxia Li Cuicui Xia Qingqing Gan Guantao He Huahui Guo Jinfeng Deng Yuqiong Wu Ray-Whay Chiu Yen Srinivasan Yegnasubramanian Scott B. Rothbart Cheng Luo Linping Wu Jinsong Liu Stephen B. Baylin Xiangqian Kong Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy Nature Communications |
| title | Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy |
| title_full | Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy |
| title_fullStr | Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy |
| title_full_unstemmed | Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy |
| title_short | Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy |
| title_sort | defining ortholog specific uhrf1 inhibition by stella for cancer therapy |
| url | https://doi.org/10.1038/s41467-024-55481-7 |
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