Inhibition of histone deacetylases induces formation of multipolar spindles and subsequent p53-dependent apoptosis in nasopharyngeal carcinoma cells.
Inhibition of histone deacetylases induces formation of multipolar spindles and subsequent p53-dependent apoptosis in nasopharyngeal carcinoma cells.
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组蛋白脱乙酰酶的抑制诱导鼻咽癌细胞中多极纺锤体的形成以及随后的 p53 依赖性细胞凋亡
DOI：
10.18632/oncotarget.9922
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Yan M;Qian YM;Yue CF;Wang ZF;Wang BC;Zhang W;Zheng FM;Liu Q
组蛋白去乙酰化酶（hdac）在癌症的发生和发展中起着至关重要的作用，为癌症治疗提供了一个有希望的靶点。hdac抑制剂MGCD0103 （MGCD）通过抑制恶性肿瘤细胞增殖和诱导细胞死亡，显示出有效的抗肿瘤活性。然而，抑制hdac诱导细胞死亡的分子机制尚未得到很好的阐明。在本研究中，我们发现MGCD在二维（2D）和三维（3D）培养的CNE1和CNE2鼻咽癌细胞中有效地恢复组蛋白乙酰化，抑制细胞生长并诱导细胞凋亡。重要的是，MGCD在有丝分裂(M)期阻滞细胞周期，形成多极纺锤体，这与激活p53介导的有丝分裂后检查点通路相关，从而诱导凋亡细胞死亡。此外，使用短干扰RNA （siRNA）抑制p53可减少mgcd诱导的细胞凋亡，这表明p53是mgcd诱导的细胞凋亡所必需的。MGCD联合MDM2抑制剂Nutlin-3在2D和3D培养的CNE2细胞中均表现出协同诱导凋亡的作用。总的来说，我们的数据显示，在鼻咽癌细胞形成多极纺锤体后，MGCD诱导p53依赖性细胞凋亡，这表明hdac和MDM2抑制剂联合治疗鼻咽癌的治疗潜力。
Histone deacetylases (HDACs) play crucial roles in the initiation and progression of cancer, offering a promising target for cancer therapy. HDACs inhibitor MGCD0103 (MGCD) exhibits effective anti-tumor activity by blocking proliferation and inducing cell death in malignant cells. However, the molecular mechanisms of HDACs inhibition induces cell death have not been well elucidated. In this study, we showed that MGCD effectively restored histone acetylation, suppressed cell growth and induced apoptosis in two-dimensional (2D) and three-dimensional (3D) cultured CNE1 and CNE2 nasopharyngeal carcinoma (NPC) cells. Importantly, MGCD arrested cell cycle at mitosis (M) phase with formation of multipolar spindles, which was associated with activated p53-mediated postmitotic checkpoint pathway to induce apoptotic cell death. Moreover, MGCD-induced apoptosis was decreased by inhibition of p53 using short interfering RNA (siRNA), suggesting that p53 was required for MGCD-induced cell apoptosis. Consistently, MGCD in combination with Nutlin-3, a MDM2 inhibitor showed synergistic effect on inducing apoptosis in 2D and 3D cultured CNE2 cells. Collectively, our data revealed that MGCD induced p53-dependent cell apoptosis following formation of multipolar spindles in NPC cells, suggesting the therapeutic potential of combinations of HDACs and MDM2 inhibitors for NPC treatment.
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影响因子：
10.5
作者：
Li, Yun;Kao, Gary D.;Lazar, Mitchell A.
通讯作者：
Lazar, Mitchell A.
组蛋白脱乙酰基酶抑制剂在癌症治疗中。
影响因子：
3.4
作者：
Lee MJ;Kim YS;Kummar S;Giaccone G;Trepel JB
通讯作者：
Trepel JB
影响因子：
56.9
作者：
CROSS, SM;SANCHEZ, CA;REID, BJ
通讯作者：
REID, BJ
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
5.3
作者：
Lanni, JS;Jacks, T
通讯作者：
Jacks, T