Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation
Abstract A recently developed synthetic retinoid abrogates proliferation and induces apoptosis of drug‐resistant malignant‐cancer‐stem‐cell‐like cells. However, the underlying mechanisms of how the synthetic retinoid induces cancer‐stem‐cell‐like cell tumor‐repopulating cell (TRC) apoptosis are elus...
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| Format: | Article |
| Language: | English |
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Wiley
2022-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202203173 |
| _version_ | 1797990308861968384 |
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| author | Yao Zhang Qi Dong Quanlin An Chumei Zhang Erfan Mohagheghian Bing Niu Feng Qi Fuxiang Wei Sihan Chen Xinman Chen Anqi Wang Xin Cao Ning Wang Junwei Chen |
| author_facet | Yao Zhang Qi Dong Quanlin An Chumei Zhang Erfan Mohagheghian Bing Niu Feng Qi Fuxiang Wei Sihan Chen Xinman Chen Anqi Wang Xin Cao Ning Wang Junwei Chen |
| author_sort | Yao Zhang |
| collection | DOAJ |
| description | Abstract A recently developed synthetic retinoid abrogates proliferation and induces apoptosis of drug‐resistant malignant‐cancer‐stem‐cell‐like cells. However, the underlying mechanisms of how the synthetic retinoid induces cancer‐stem‐cell‐like cell tumor‐repopulating cell (TRC) apoptosis are elusive. Here, it is shown that although the retinoid and conventional anticancer drugs cisplatin, all‐trans retinoic acid, and tazarotene all inhibit cytoskeletal tension and decondense chromatin prior to inducing TRC apoptosis, half‐maximal inhibitory concentration of the retinoid is 20‐fold lower than those anticancer drugs. The synthetic retinoid induces retinoic acid receptor gamma (RARγ) translocation from the nucleus to the cytoplasm, leading to reduced RARγ binding to Cdc42 promoter and Cdc42 downregulation, which decreases filamentous‐actin (F‐actin) and inhibits cytoskeletal tension. Elevating F‐actin or upregulating histone 3 lysine 9 trimethylation decreases retinoid‐induced DNA damage and apoptosis of TRCs. The combinatorial treatment with a chromatin decondensation molecule and the retinoid inhibits tumor metastasis in mice more effectively than the synthetic retinoid alone. These findings suggest a strategy of lowering cell tension and decondensing chromatin to enhance DNA damage to abrogate metastasis of cancer‐stem‐cell‐like cells with high efficacy. |
| first_indexed | 2024-04-11T08:33:31Z |
| format | Article |
| id | doaj.art-93477889198c45418e30810334a96d1f |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-11T08:33:31Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-93477889198c45418e30810334a96d1f2022-12-22T04:34:24ZengWileyAdvanced Science2198-38442022-11-01931n/an/a10.1002/advs.202203173Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin DecondensationYao Zhang0Qi Dong1Quanlin An2Chumei Zhang3Erfan Mohagheghian4Bing Niu5Feng Qi6Fuxiang Wei7Sihan Chen8Xinman Chen9Anqi Wang10Xin Cao11Ning Wang12Junwei Chen13Key Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaInstitute of Clinical Science Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaDepartment of Mechanical Science and Engineering The Grainger College of Engineering University of Illinois at Urbana‐Champaign Urbana IL 61801 USASchool of Life Sciences Shanghai University 99 Shangda Road Shanghai 200444 ChinaInstitute of Clinical Science Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaInstitute of Clinical Science Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaDepartment of Mechanical Science and Engineering The Grainger College of Engineering University of Illinois at Urbana‐Champaign Urbana IL 61801 USAKey Laboratory of Molecular Biophysics of the Ministry of Education Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaAbstract A recently developed synthetic retinoid abrogates proliferation and induces apoptosis of drug‐resistant malignant‐cancer‐stem‐cell‐like cells. However, the underlying mechanisms of how the synthetic retinoid induces cancer‐stem‐cell‐like cell tumor‐repopulating cell (TRC) apoptosis are elusive. Here, it is shown that although the retinoid and conventional anticancer drugs cisplatin, all‐trans retinoic acid, and tazarotene all inhibit cytoskeletal tension and decondense chromatin prior to inducing TRC apoptosis, half‐maximal inhibitory concentration of the retinoid is 20‐fold lower than those anticancer drugs. The synthetic retinoid induces retinoic acid receptor gamma (RARγ) translocation from the nucleus to the cytoplasm, leading to reduced RARγ binding to Cdc42 promoter and Cdc42 downregulation, which decreases filamentous‐actin (F‐actin) and inhibits cytoskeletal tension. Elevating F‐actin or upregulating histone 3 lysine 9 trimethylation decreases retinoid‐induced DNA damage and apoptosis of TRCs. The combinatorial treatment with a chromatin decondensation molecule and the retinoid inhibits tumor metastasis in mice more effectively than the synthetic retinoid alone. These findings suggest a strategy of lowering cell tension and decondensing chromatin to enhance DNA damage to abrogate metastasis of cancer‐stem‐cell‐like cells with high efficacy.https://doi.org/10.1002/advs.202203173cancer stem cellscell apoptosischromatin decondensationdrug efficacytension force |
| spellingShingle | Yao Zhang Qi Dong Quanlin An Chumei Zhang Erfan Mohagheghian Bing Niu Feng Qi Fuxiang Wei Sihan Chen Xinman Chen Anqi Wang Xin Cao Ning Wang Junwei Chen Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation Advanced Science cancer stem cells cell apoptosis chromatin decondensation drug efficacy tension force |
| title | Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation |
| title_full | Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation |
| title_fullStr | Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation |
| title_full_unstemmed | Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation |
| title_short | Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation |
| title_sort | synthetic retinoid kills drug resistant cancer stem cells via inducing rarγ translocation mediated tension reduction and chromatin decondensation |
| topic | cancer stem cells cell apoptosis chromatin decondensation drug efficacy tension force |
| url | https://doi.org/10.1002/advs.202203173 |
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