CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation
Abstract Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and dr...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2025-06-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-025-02361-3 |
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| _version_ | 1849691412169228288 |
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| author | Jianghua Li Lu Xu Jiayu Wang Xuning Wang Yuting Lin Alex Yutian Zou Fangli Ren Yinyin Wang Jun Li Zhijie Chang |
| author_facet | Jianghua Li Lu Xu Jiayu Wang Xuning Wang Yuting Lin Alex Yutian Zou Fangli Ren Yinyin Wang Jun Li Zhijie Chang |
| author_sort | Jianghua Li |
| collection | DOAJ |
| description | Abstract Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC. Graphical Abstract |
| format | Article |
| id | doaj-art-cd1a2e2630144250a17df470fc276e58 |
| institution | DOAJ |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-cd1a2e2630144250a17df470fc276e582025-08-20T03:21:02ZengBMCMolecular Cancer1476-45982025-06-0124114010.1186/s12943-025-02361-3CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulationJianghua Li0Lu Xu1Jiayu Wang2Xuning Wang3Yuting Lin4Alex Yutian Zou5Fangli Ren6Yinyin Wang7Jun Li8Zhijie Chang9State Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of General Surgery, General Hospital of Northern Theater CommandState Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityCollege of Letters & Science, University of California BerkeleyState Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityJinfeng LaboratoryState Key Laboratory of Membrane Biology, School of Basic Medical Sciences, School of Medicine, Tsinghua UniversityAbstract Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC. Graphical Abstracthttps://doi.org/10.1186/s12943-025-02361-3 |
| spellingShingle | Jianghua Li Lu Xu Jiayu Wang Xuning Wang Yuting Lin Alex Yutian Zou Fangli Ren Yinyin Wang Jun Li Zhijie Chang CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation Molecular Cancer |
| title | CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation |
| title_full | CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation |
| title_fullStr | CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation |
| title_full_unstemmed | CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation |
| title_short | CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation |
| title_sort | crept is required for the metastasis of triple negative breast cancer through a co operational chromatin loop based gene regulation |
| url | https://doi.org/10.1186/s12943-025-02361-3 |
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