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Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling
Osteosarcoma is the most common primary malignant bone tumor, and there are few ideal clinically available drugs. The bromodomain and extraterminal domain (BET) protein is an emerging target for aggressive cancer, but therapies targeting the BET in osteosarcoma have been unsuccessful in clinical tri...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219214/ https://www.ncbi.nlm.nih.gov/pubmed/34168981 http://dx.doi.org/10.3389/fonc.2021.642134 |
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author | Jiang, Yafei Wang, Gangyang Mu, Haoran Ma, Xiaojun Wang, Zhuoying Lv, Yu Zhang, Tao Xu, Jing Wang, Jinzeng Li, Yunqi Han, Jing Yang, Mengkai Wang, Zongyi Zeng, Ke Jin, Xinmeng Xue, Song Yin, Mingzhu Sun, Wei Hua, Yingqi Cai, Zhengdong |
author_facet | Jiang, Yafei Wang, Gangyang Mu, Haoran Ma, Xiaojun Wang, Zhuoying Lv, Yu Zhang, Tao Xu, Jing Wang, Jinzeng Li, Yunqi Han, Jing Yang, Mengkai Wang, Zongyi Zeng, Ke Jin, Xinmeng Xue, Song Yin, Mingzhu Sun, Wei Hua, Yingqi Cai, Zhengdong |
author_sort | Jiang, Yafei |
collection | PubMed |
description | Osteosarcoma is the most common primary malignant bone tumor, and there are few ideal clinically available drugs. The bromodomain and extraterminal domain (BET) protein is an emerging target for aggressive cancer, but therapies targeting the BET in osteosarcoma have been unsuccessful in clinical trials to date, and further exploration of specific BET inhibitors is of great significance. In our study, we demonstrated that NHWD-870, a potent BET inhibitor in a phase I clinical trial, significantly inhibited tumor proliferation and promoted cell apoptosis by reversing the oncogenic signature in osteosarcoma. More importantly, we identified NHWD-870 impeded binding of BRD4 to the promoter of GP130 leading to diminished activation of JAK/STAT3 signaling pathway. Furthermore, GP130 knockdown significantly sensitizes the chemosensitivity in vitro. In OS cell-derived xenografts, NHWD-870 effectively inhibited the growth of osteosarcoma. Beyond that, NHWD-870 effectively inhibited the differentiation and maturation of precursor osteoclasts in vitro and attenuated osteoclast-mediated bone loss in vivo. Finally, we confirmed the efficacy of synthetic lethal effects of NHWD-870 and cisplatin in antagonizing osteosarcoma in a preclinical PDX model. Taken together, these findings demonstrate that NHWD-870, as an effective BET inhibitor, may be a potential candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity. In addition, NHWD-870 appears to be a promising therapeutic strategy for bone-associated tumors, as it interferes with the vicious cycle of tumor progression and bone destruction. |
format | Online Article Text |
id | pubmed-8219214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82192142021-06-23 Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling Jiang, Yafei Wang, Gangyang Mu, Haoran Ma, Xiaojun Wang, Zhuoying Lv, Yu Zhang, Tao Xu, Jing Wang, Jinzeng Li, Yunqi Han, Jing Yang, Mengkai Wang, Zongyi Zeng, Ke Jin, Xinmeng Xue, Song Yin, Mingzhu Sun, Wei Hua, Yingqi Cai, Zhengdong Front Oncol Oncology Osteosarcoma is the most common primary malignant bone tumor, and there are few ideal clinically available drugs. The bromodomain and extraterminal domain (BET) protein is an emerging target for aggressive cancer, but therapies targeting the BET in osteosarcoma have been unsuccessful in clinical trials to date, and further exploration of specific BET inhibitors is of great significance. In our study, we demonstrated that NHWD-870, a potent BET inhibitor in a phase I clinical trial, significantly inhibited tumor proliferation and promoted cell apoptosis by reversing the oncogenic signature in osteosarcoma. More importantly, we identified NHWD-870 impeded binding of BRD4 to the promoter of GP130 leading to diminished activation of JAK/STAT3 signaling pathway. Furthermore, GP130 knockdown significantly sensitizes the chemosensitivity in vitro. In OS cell-derived xenografts, NHWD-870 effectively inhibited the growth of osteosarcoma. Beyond that, NHWD-870 effectively inhibited the differentiation and maturation of precursor osteoclasts in vitro and attenuated osteoclast-mediated bone loss in vivo. Finally, we confirmed the efficacy of synthetic lethal effects of NHWD-870 and cisplatin in antagonizing osteosarcoma in a preclinical PDX model. Taken together, these findings demonstrate that NHWD-870, as an effective BET inhibitor, may be a potential candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity. In addition, NHWD-870 appears to be a promising therapeutic strategy for bone-associated tumors, as it interferes with the vicious cycle of tumor progression and bone destruction. Frontiers Media S.A. 2021-06-08 /pmc/articles/PMC8219214/ /pubmed/34168981 http://dx.doi.org/10.3389/fonc.2021.642134 Text en Copyright © 2021 Jiang, Wang, Mu, Ma, Wang, Lv, Zhang, Xu, Wang, Li, Han, Yang, Wang, Zeng, Jin, Xue, Yin, Sun, Hua and Cai https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Jiang, Yafei Wang, Gangyang Mu, Haoran Ma, Xiaojun Wang, Zhuoying Lv, Yu Zhang, Tao Xu, Jing Wang, Jinzeng Li, Yunqi Han, Jing Yang, Mengkai Wang, Zongyi Zeng, Ke Jin, Xinmeng Xue, Song Yin, Mingzhu Sun, Wei Hua, Yingqi Cai, Zhengdong Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling |
title | Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling |
title_full | Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling |
title_fullStr | Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling |
title_full_unstemmed | Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling |
title_short | Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling |
title_sort | bromodomain inhibition attenuates the progression and sensitizes the chemosensitivity of osteosarcoma by repressing gp130/stat3 signaling |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219214/ https://www.ncbi.nlm.nih.gov/pubmed/34168981 http://dx.doi.org/10.3389/fonc.2021.642134 |
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