Understanding the mechanisms of advanced metastasis in osteosarcoma (OS) cell is important for the targeted treatment and drug development. Emerging evidence shows that epigenetic factors such as histone deacetylases (HDACs) are involved in the progression and chemoresistance of OS, while their roles are largely unknown. Our data showed that the expression of HDAC2, while not HDAC1, 4, or 8, was significantly increased in OS cells and tissues. OS patients with increased expression of HDAC2 showed reduced overall survival with p value of 0.0001. Targeted inhibition of HDAC2 suppressed the in vitro migration and invasion of OS cells. Our data showed that the inhibition of HDAC2 can decrease the expression and transcription of interleukin-6 (IL-6) in OS cells. Overexpression of IL-6 can reverse si-HDAC2-induced suppression of cell migration. Mechanistical studies showed that inhibition of HDAC2 decreased the phosphorylation and nuclear accumulation of p65, the key factor of NF-κB complex responsible for the transcription of IL-6. This was due to that HDAC2 can activate the transcription of IKK-β in OS cells. Collectively, our data showed that HDAC2-activated NF-κB can increase the expression of IL-6 in OS cells, which resulted in the promotion of cell migration. It suggested that targeted inhibition of HDAC2/NF-κB/IL-6 might be a potential approach for OS therapy.

中文翻译：

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HDAC2介导的IL-6上调触发骨肉瘤细胞的迁移。

了解骨肉瘤（OS）细胞中晚期转移的机制对于靶向治疗和药物开发很重要。新兴证据表明，表观遗传因素（例如组蛋白脱乙酰基酶（HDACs））参与了OS的进程和化学耐药性，而它们的作用在很大程度上尚不清楚。我们的数据表明，OS细胞和组织中HDAC2的表达显着增加，而HDAC1、4或8则没有。HDAC2表达增加的OS患者显示p降低了总生存率值0.0001。HDAC2的靶向抑制抑制了OS细胞的体外迁移和侵袭。我们的数据表明，抑制HDAC2可以降低OS细胞中白介素6（IL-6）的表达和转录。IL-6的过表达可以逆转si-HDAC2诱导的细胞迁移抑制。机理研究表明，抑制HDAC2会降低p65的磷酸化和核积累，而p65是负责IL-6转录的NF-κB复合体的关键因素。这是由于HDAC2可以激活OS细胞中IKK-β的转录。总体而言，我们的数据表明，HDAC2激活的NF-κB可以增加OS细胞中IL-6的表达，从而促进细胞迁移。这表明靶向抑制HDAC2 /NF-κB/ IL-6可能是OS治疗的潜在方法。