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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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.
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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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