SIRT2 downregulation confers resistance to microtubule inhibitors by prolonging chronic mitotic arrest
SIRT2 downregulation confers resistance to microtubule inhibitors by prolonging chronic mitotic arrest
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DOI：
10.4161/cc.8.8.8245
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发表时间：
2009-04-15
期刊：
影响因子：
4.3
通讯作者：
Oshimura, Mitsuo
中科院分区：
文献类型：
--
作者：
Inoue, Toshiaki;Nakayama, Yuji;Oshimura, Mitsuo
我们先前鉴定了SIRT2，一种微管蛋白和组蛋白H4的脱乙酰酶，作为神经胶质瘤中下调的蛋白质，并报道了外源表达的SIRT2在进入有丝分裂之前阻止细胞周期，以防止响应微管抑制剂（MTIs）如诺考达唑的染色体不稳定性，这是先前报道的CHFR蛋白的特征。我们在此研究了SIRT2下调对使用HCT 116细胞的MTI敏感性的影响，HCT 116细胞是用于研究检查点的有丝分裂检查点精通的近二倍体癌细胞系。我们发现，SIRT2下调赋予耐MTIs以及BubR1，一个良好的特征有丝分裂检查点蛋白，虽然通过不同的机制。虽然BubR1抑制废除了纺锤体检查点功能，这是从纺锤体检查点释放后细胞死亡的必要条件，但SIRT2下调延长了有丝分裂检查点持续激活的慢性有丝分裂停滞，因此防止了从慢性有丝分裂停滞释放后向次要结果（包括细胞死亡）的转变。与这一观点一致，在诺考达唑存在下，BubR1下调在有丝分裂调控方面优于SIRT2敲低。这些结果表明，SIRT2的功能是在用MTIs处理的细胞中释放慢性有丝分裂停滞，导致其他结果。我们还发现，在纺锤体检查点功能改变之前，SIRT2下调引起了对诺考达唑的响应的中心体片段化，这不仅意味着SIRT2在暴露于由MTIs引起的有丝分裂应激后维持中心体的新功能，而且还存在中心体介导的信号通路来维持纺锤体检查点。因此，这项研究强调了一种新的途径，导致耐药性的MTIs，其中SIRT2下调参与。
We previously identified SIRT2, a deacetylase for tubulin and histone H4, as a protein downregulated in gliomas, and reported that exogenously-expressed SIRT2 arrests the cell cycle prior to entry into mitosis to prevent chromosomal instability in response to microtubule inhibitors (MTIs) such as nocodazole, characteristics previously reported for the CHFR protein. We herein investigated the effects of SIRT2 downregulation on sensitivity to MTIs using HCT116 cells, a mitotic checkpoint-proficient near-diploid cancer cell line used for studying checkpoints. We found that SIRT2 downregulation confers resistance to MTIs as well as that of BubR1, a well-characterized mitotic checkpoint protein, though by a different mechanism. While BubR1 suppression abolished spindle checkpoint functions, which is a requirement for cell death after release from the spindle checkpoint, SIRT2 downregulation prolonged chronic mitotic arrest from sustained activation of the mitotic checkpoint and consequently prevented a shift to secondary outcomes, including cell death, after release from chronic mitotic arrest. Consistent with this notion, BubR1 downregulation was dominant over SIRT2 knockdown in regard to mitotic regulation in the presence of nocodazole. These results suggest that SIRT2 functions to release chronic mitotic arrest in cells treated with MTIs, leading to other outcomes. We also found that SIRT2 downregulation caused centrosome fragmentation in response to nocodazole prior to the alteration in spindle checkpoint function, implying not only a novel function of SIRT2 for centrosome maintenance upon exposure to mitotic stress caused by MTIs, but also the existence of a centrosome-mediated signaling pathway to sustain the spindle checkpoint. Therefore, this study highlights a novel pathway leading to resistance to MTIs, in which SIRT2 downregulation participates.