Tian Jia-Ming, Dong Yi-He, Li Zi, Zhou Yong, Huang Jun
Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Orthopedics, The Affiliation Hospital of Yiyang Medical College, YiYang, Hunan, China.
Cell Death Discov. 2025 Jun 10;11(1):272. doi: 10.1038/s41420-025-02541-6.
Osteosarcoma (OS) is deemed as hormone-dependent neoplasm. Here we explored its latent mechanisms governing the interactions between specific molecules and hormones involved in OS progression. Through multiplex IHC analysis in TMA, bioinformatics analysis, and a series of in vitro and in vivo molecular assays, we identified BRD4 and sex steroid receptors were positively expressed in clinical OS tissues, simultaneously BRD4 and AR expression were elevated in the osteoblastic subtype, while ERβ predominated in the fibroblastic subtype. GEO database revealed a positive correlation between BRD4 and AR expression, while no correlation was found with ERβ expression. In vitro studies demonstrated that DHT stimulation resulted in a significant upregulation of AR and BRD4 protein expression, subsequently promoting the proliferation of OS cells. ChIP-sequencing and dual-luciferase reporter assays revealed that DHT treatment increased the distribution of BRD4 on chromatin and its overlap with AR, facilitating the formation of the AR-BRD4 transcriptional regulatory complex, which significantly increased transcription levels of AR target genes, such as PLCB4. Moreover, experiments conducted in nude mice indicated that BRD4 inhibitor, (+)-JQ1 decreased the expression of AR-related genes and inhibited OS cell growth in vivo. In conclusion, elevated expression of BRD4 in OS cells induced by androgens participates in AR-related transcriptional regulatory processes, facilitating the malignant progression of OS.
骨肉瘤（OS）被认为是激素依赖性肿瘤。在此，我们探究了其在OS进展过程中特定分子与激素相互作用的潜在机制。通过组织芯片（TMA）的多重免疫组化分析、生物信息学分析以及一系列体外和体内分子实验，我们发现BRD4和性类固醇受体在临床OS组织中呈阳性表达，同时在成骨细胞亚型中BRD4和雄激素受体（AR）表达升高，而在纤维母细胞亚型中雌激素受体β（ERβ）占主导。基因表达综合数据库（GEO）显示BRD4与AR表达呈正相关，而与ERβ表达无相关性。体外研究表明，双氢睾酮（DHT）刺激导致AR和BRD4蛋白表达显著上调，随后促进OS细胞增殖。染色质免疫沉淀测序（ChIP-sequencing）和双荧光素酶报告基因检测显示，DHT处理增加了BRD4在染色质上的分布及其与AR的重叠，促进了AR - BRD4转录调节复合物的形成，这显著增加了AR靶基因如磷脂酶Cβ4（PLCB4）的转录水平。此外，在裸鼠中进行的实验表明，BRD4抑制剂（+）-JQ1降低了AR相关基因的表达并在体内抑制了OS细胞生长。总之，雄激素诱导的OS细胞中BRD4表达升高参与了AR相关的转录调节过程，促进了OS的恶性进展。
