Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma
Abstract Acquired resistance to chemotherapy is one of the major causes of mortality in advanced nasopharyngeal carcinoma (NPC). However, effective strategies are limited and the underlying molecular mechanisms remain elusive. In this study, through transcriptomic profiling analysis of 23 tumor tiss...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06028-z |
| _version_ | 1797743968849494016 |
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| author | Lizhen Liu Peng Deng Sailan Liu Jing Han Hong Rong Xiao Peiyong Guan Yali Wang Peili Wang Jiuping Gao Jinghong Chen Yichen Sun Jianfeng Chen Hai-Qiang Mai Jing Tan |
| author_facet | Lizhen Liu Peng Deng Sailan Liu Jing Han Hong Rong Xiao Peiyong Guan Yali Wang Peili Wang Jiuping Gao Jinghong Chen Yichen Sun Jianfeng Chen Hai-Qiang Mai Jing Tan |
| author_sort | Lizhen Liu |
| collection | DOAJ |
| description | Abstract Acquired resistance to chemotherapy is one of the major causes of mortality in advanced nasopharyngeal carcinoma (NPC). However, effective strategies are limited and the underlying molecular mechanisms remain elusive. In this study, through transcriptomic profiling analysis of 23 tumor tissues, we found that NOTCH3 was aberrantly highly expressed in chemoresistance NPC patients, with NOTCH3 overexpression being positively associated with poor clinical outcome. Mechanistically, using an established NPC cellular model, we demonstrated that enhancer remodeling driven aberrant hyperactivation of NOTCH3 in chemoresistance NPC. We further showed that NOTCH3 upregulates SLUG to induce chemo-resistance of NPC cells and higher expression of SLUG have poorer prognosis. Genetic or pharmacological perturbation of NOTCH3 conferred chemosensitivity of NPC in vitro and overexpression of NOTCH3 enhanced chemoresistance of NPC in vivo. Together, these data indicated that genome-wide enhancer reprogramming activates NOTCH3 to confer chemoresistance of NPC, suggesting that targeting NOTCH3 may provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC. |
| first_indexed | 2024-03-12T15:03:08Z |
| format | Article |
| id | doaj.art-1bdffcc862c14d5fbf6c15dd5b641646 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T15:03:08Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-1bdffcc862c14d5fbf6c15dd5b6416462023-08-13T11:24:41ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811210.1038/s41419-023-06028-zEnhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinomaLizhen Liu0Peng Deng1Sailan Liu2Jing Han Hong3Rong Xiao4Peiyong Guan5Yali Wang6Peili Wang7Jiuping Gao8Jinghong Chen9Yichen Sun10Jianfeng Chen11Hai-Qiang Mai12Jing Tan13Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterCancer and Stem Cell Biology, Duke-NUS Medical SchoolState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterGenome Institute of Singapore, A*STARState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterAbstract Acquired resistance to chemotherapy is one of the major causes of mortality in advanced nasopharyngeal carcinoma (NPC). However, effective strategies are limited and the underlying molecular mechanisms remain elusive. In this study, through transcriptomic profiling analysis of 23 tumor tissues, we found that NOTCH3 was aberrantly highly expressed in chemoresistance NPC patients, with NOTCH3 overexpression being positively associated with poor clinical outcome. Mechanistically, using an established NPC cellular model, we demonstrated that enhancer remodeling driven aberrant hyperactivation of NOTCH3 in chemoresistance NPC. We further showed that NOTCH3 upregulates SLUG to induce chemo-resistance of NPC cells and higher expression of SLUG have poorer prognosis. Genetic or pharmacological perturbation of NOTCH3 conferred chemosensitivity of NPC in vitro and overexpression of NOTCH3 enhanced chemoresistance of NPC in vivo. Together, these data indicated that genome-wide enhancer reprogramming activates NOTCH3 to confer chemoresistance of NPC, suggesting that targeting NOTCH3 may provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC.https://doi.org/10.1038/s41419-023-06028-z |
| spellingShingle | Lizhen Liu Peng Deng Sailan Liu Jing Han Hong Rong Xiao Peiyong Guan Yali Wang Peili Wang Jiuping Gao Jinghong Chen Yichen Sun Jianfeng Chen Hai-Qiang Mai Jing Tan Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma Cell Death and Disease |
| title | Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma |
| title_full | Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma |
| title_fullStr | Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma |
| title_full_unstemmed | Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma |
| title_short | Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma |
| title_sort | enhancer remodeling activates notch3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma |
| url | https://doi.org/10.1038/s41419-023-06028-z |
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