Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling

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.

Osteosarcoma Multi-omics Landscape and Subtypes

“…These genes show signi cant difference in the pro les of SCNA, expression, and methylation across three subgroups for both training and validation dataset, suggesting their potential roles in differentiating the OS patients. Among them, MLLT3[16], ATM(ataxia-telangiectasia mutated)/ATR (ataxia-telangiectasia and Rad3 related) [17][18][19], DDX10 [20][21][22], CASP1 [9] and BRD4 [23,24] and have been extensively studied and show to be associated with pathogenesis or clinical outcomes in osteosarcoma. Additionally, UBASH3B [25,26], CASP1 [27], CARM1[28-31], CHAF1B [32,33] and PCNT [34,35] have been studied in other cancers.…”

Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies

“…In OS, apatinib suppresses the OS cell growth, blocks cells in the G0/G1 phase, 231 and induces apoptosis and autophagy 232 . NHWD‐870 disrupts the binding affinity of BRD4 to the upstream receptor GP130 promoter region of STAT3, impairs upstream signaling, blocks STAT3 dimerization, and induces apoptosis 233 …”

“… 232 NHWD‐870 disrupts the binding affinity of BRD4 to the upstream receptor GP130 promoter region of STAT3, impairs upstream signaling, blocks STAT3 dimerization, and induces apoptosis. 233 …”

Unraveling the epigenetic landscape of pulmonary arterial hypertension: implications for personalized medicine development

“…Previous studies have reported that BRD4 activates several downstream targets including the MAPK/ERK pathway, which regulates cell growth and differentiation. Additionally, BRD4 has been shown to interact with other proteins and transcription factors involved in cell proliferation, such as STAT3 [ 72 ].…”