Zhao Gang, Wang Guoliang, Bai Hongmin, Li Tiandong, Gong Fanghe, Yang Huan, Wen Jinchong, Wang Weimin
Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
Eur J Pharmacol. 2017 May 5;802:20-26. doi: 10.1016/j.ejphar.2017.02.035. Epub 2017 Feb 20.
Histone deacetylases (HDACs) have been suggested to be potential therapeutic targets for cancer treatment. Recent studies revealed that HDAC8 expression was associated with poor prognostic markers and poor overall survival rate of neuroblastoma (NB). Our present study revealed that among the four members of class I HDACs, HDAC8 is significantly over expressed in NB cells as compared with the normal fibroblast 3T3 cells or primary normal human astrocytes (NHA) cells. Targeted inhibition of HDAC8 by its specific siRNA (si-HDAC8) can inhibit the in vitro growth of NB cells. Furthermore, si-HDAC8 significantly increases the sensitivity of NB cells to doxorubicin (Dox). Silencing of HDAC8 can increase the expression of miR-137, which has been suggested to mediate the Dox sensitivity of NB cells. Knockdown of miR-137 can attenuate si-HDAC8 enhanced Dox sensitivity. Further, si-HDAC8 can also inhibit the expression of multi-drug resistance gene 1 (MDR1). While knockdown of miR-137 can attenuate si-HDAC8 induced down regulation of MDR1. Collectively, our data revealed that targeted inhibition of HDAC8 can suppress the growth of NB cells and increase Dox sensitivity via up regulation of miR-137 and suppression of MDR1. Therefor, combination of HDAC8 inhibitor will be helpful to elevate the treatment outcome of NB patients.
组蛋白去乙酰化酶（HDACs）被认为是癌症治疗的潜在靶点。最近的研究表明，HDAC8的表达与神经母细胞瘤（NB）的不良预后标志物和较低的总生存率相关。我们目前的研究表明，在I类HDACs的四个成员中，与正常成纤维细胞3T3细胞或原代正常人星形胶质细胞（NHA）相比，HDAC8在NB细胞中显著过表达。通过其特异性小干扰RNA（si-HDAC8）对HDAC8进行靶向抑制可抑制NB细胞的体外生长。此外，si-HDAC8显著增加NB细胞对阿霉素（Dox）的敏感性。HDAC8的沉默可增加miR-137的表达，有人认为miR-137可介导NB细胞对Dox的敏感性。敲低miR-137可减弱si-HDAC8增强的Dox敏感性。此外，si-HDAC8还可抑制多药耐药基因1（MDR1）的表达。而敲低miR-137可减弱si-HDAC8诱导的MDR1下调。总的来说，我们的数据表明，对HDAC8进行靶向抑制可通过上调miR-137和抑制MDR1来抑制NB细胞的生长并增加对Dox的敏感性。因此，HDAC8抑制剂的联合使用将有助于提高NB患者的治疗效果。
