Frontiers in Oncology (Jun 2021)
Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling
- Yafei Jiang,
- Yafei Jiang,
- Gangyang Wang,
- Gangyang Wang,
- Haoran Mu,
- Haoran Mu,
- Xiaojun Ma,
- Xiaojun Ma,
- Zhuoying Wang,
- Zhuoying Wang,
- Yu Lv,
- Tao Zhang,
- Tao Zhang,
- Jing Xu,
- Jing Xu,
- Jinzeng Wang,
- Yunqi Li,
- Jing Han,
- Jing Han,
- Mengkai Yang,
- Mengkai Yang,
- Zongyi Wang,
- Zongyi Wang,
- Ke Zeng,
- Ke Zeng,
- Xinmeng Jin,
- Xinmeng Jin,
- Song Xue,
- Song Xue,
- Mingzhu Yin,
- Wei Sun,
- Wei Sun,
- Yingqi Hua,
- Yingqi Hua,
- Zhengdong Cai,
- Zhengdong Cai
Affiliations
- Yafei Jiang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Yafei Jiang
- Shanghai Bone Tumor Institution, Shanghai, China
- Gangyang Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Gangyang Wang
- Shanghai Bone Tumor Institution, Shanghai, China
- Haoran Mu
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Haoran Mu
- Shanghai Bone Tumor Institution, Shanghai, China
- Xiaojun Ma
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Xiaojun Ma
- Shanghai Bone Tumor Institution, Shanghai, China
- Zhuoying Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Zhuoying Wang
- Shanghai Bone Tumor Institution, Shanghai, China
- Yu Lv
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Tao Zhang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Tao Zhang
- Shanghai Bone Tumor Institution, Shanghai, China
- Jing Xu
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Jing Xu
- Shanghai Bone Tumor Institution, Shanghai, China
- Jinzeng Wang
- National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai, China
- Yunqi Li
- National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai, China
- Jing Han
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Jing Han
- Shanghai Bone Tumor Institution, Shanghai, China
- Mengkai Yang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Mengkai Yang
- Shanghai Bone Tumor Institution, Shanghai, China
- Zongyi Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Zongyi Wang
- Shanghai Bone Tumor Institution, Shanghai, China
- Ke Zeng
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Ke Zeng
- Shanghai Bone Tumor Institution, Shanghai, China
- Xinmeng Jin
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Xinmeng Jin
- Shanghai Bone Tumor Institution, Shanghai, China
- Song Xue
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Song Xue
- Shanghai Bone Tumor Institution, Shanghai, China
- Mingzhu Yin
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Wei Sun
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Wei Sun
- Shanghai Bone Tumor Institution, Shanghai, China
- Yingqi Hua
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Yingqi Hua
- Shanghai Bone Tumor Institution, Shanghai, China
- Zhengdong Cai
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Zhengdong Cai
- Shanghai Bone Tumor Institution, Shanghai, China
- DOI
- https://doi.org/10.3389/fonc.2021.642134
- Journal volume & issue
-
Vol. 11
Abstract
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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