Orthopedic Department, TCM Hospital of Rizhao, Rizhao, 276800, China.
Orthopedic Department, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, No.639 Zhizao Ju Road, Shanghai, 200011, China.
Cell Biol Toxicol. 2019 Oct;35(5):423-433. doi: 10.1007/s10565-019-09459-7. Epub 2019 Jan 31.
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.
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至关重要。新出现的证据表明，表观遗传因素如组蛋白去乙酰化酶（HDACs）参与了 OS 的进展和化疗耐药性，但其作用在很大程度上尚不清楚。我们的数据显示，HDAC2 的表达（而非 HDAC1、4 或 8）在 OS 细胞和组织中显著增加。HDAC2 表达增加的 OS 患者的总生存率降低，p 值为 0.0001。HDAC2 的靶向抑制抑制了 OS 细胞的体外迁移和侵袭。我们的数据显示，HDAC2 的抑制可降低 OS 细胞中白细胞介素 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。机制研究表明，HDAC2 的抑制降低了 p65 的磷酸化和核积累，p65 是负责 IL-6 转录的 NF-κB 复合物的关键因子。这是因为 HDAC2 可以在 OS 细胞中激活 IKK-β 的转录。总之，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 治疗的一种潜在方法。
