HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma
HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma
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HDAC6 促进胶质母细胞瘤细胞增殖并赋予替莫唑胺耐药性
DOI：
10.1016/j.canlet.2016.06.001
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发表时间：
2016
期刊：
影响因子：
9.7
通讯作者：
Xie Conghua
中科院分区：
文献类型：
--
作者：
Wang Zhihao;Hu Pengchao;Tang Fang;Lian Haiwei;Chen Xiong;Zhang Yingying;He Xiaohua;Liu Wanhong;Xie Conghua
组蛋白去乙酰化酶被认为是癌症治疗药物开发中最有前途的靶标之一。组蛋白去乙酰化酶6（HDAC 6）是一种独特的细胞质酶，通过其去乙酰化酶和泛素结合活性调节参与肿瘤发生的许多生物学过程。在这里，我们报告HDAC6在胶质母细胞瘤组织和细胞系中过表达。HDAC6的过表达促进胶质母细胞瘤细胞的增殖和球体形成。HDAC6过表达赋予对替莫唑胺（TMZ）介导的细胞增殖抑制和凋亡诱导的抗性。相反，HDAC6的敲低抑制细胞增殖，损害球状体形成并使胶质母细胞瘤细胞对TMZ敏感。选择性抑制剂对HDAC6脱乙酰酶活性的抑制抑制胶质母细胞瘤细胞的增殖并诱导凋亡。HDAC6选择性抑制剂可使胶质母细胞瘤细胞对TMZ敏感。此外，我们发现HDAC6介导的EGFR稳定可能部分解释了其在胶质母细胞瘤中的致癌作用。TMZ耐药胶质母细胞瘤细胞显示HDAC 6表达更高，EGFR活化更多。HDAC6抑制剂降低EGFR蛋白水平并损害EGFR途径的活化。总之，我们的结果表明，HDAC 6的抑制可能是一个有前途的策略，用于治疗胶质母细胞瘤。
Histone deacetylases are considered to be among the most promising targets in drug development for cancer therapy. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes involved in tumorigenesis through its deacetylase and ubiquitin-binding activities. Here, we report that HDAC6 is overexpressed in glioblastoma tissues and cell lines. Overexpression of HDAC6 promotes the proliferation and spheroid formation of glioblastoma cells. HDAC6 overexpression confers resistance to temozolomide (TMZ) mediated cell proliferation inhibition and apoptosis induction. Conversely, knockdown of HDAC6 inhibits cell proliferation, impairs spheroid formation and sensitizes glioblastoma cells to TMZ. The inhibition of HDAC6 deacetylase activity by selective inhibitors inhibits the proliferation of glioblastoma cells and induces apoptosis. HDAC6 selective inhibitors can sensitize glioblastoma cells to TMZ. Moreover, we showed that HDAC6 mediated EGFR stabilization might partly account for its oncogenic role in glioblastoma. TMZ resistant glioblastoma cells showed higher expression of HDAC6 and more activation of EGFR. HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of glioblastoma.