Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β ( TGFβ) Receptor II Leading to Cancer Cell Death
Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β ( TGFβ) Receptor II Leading to Cancer Cell Death
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DOI：
10.1074/jbc.m110.212035
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发表时间：
2011-09-02
影响因子：
4.8
通讯作者：
Brattain, Michael G.
中科院分区：
文献类型：
--
作者：
Chowdhury, Sanjib;Howell, Gillian M.;Brattain, Michael G.
Survivin是一种癌症相关基因，功能是促进细胞存活、细胞分裂和血管生成，是预后不良的标志。组蛋白脱乙酰酶抑制剂诱导癌细胞中的细胞凋亡和表观遗传沉默的肿瘤抑制基因的重新表达。在组蛋白去乙酰化酶抑制剂belinostat诱导的肿瘤抑制基因转化生长因子β受体II(TGFβRII)表达增加的同时，我们观察到Survivin表达被抑制。我们研究了转化生长因子β信号再激活下游贝力诺下调Survivin的分子机制。我们确定了两种机制。在早期时间点，Survivin蛋白半衰期随着其蛋白酶体的降解而缩短。我们观察到，在转化生长因子β信号依赖的机制中，贝利诺斯特在早期的时间点激活了蛋白激酶A。在较长时间(48h)后，贝利诺他也降低了Survivin基因的表达。我们发现贝利诺通过转化生长因子β/蛋白激酶A信号通路介导细胞死亡。诱导转化生长因子β受体结合Survivin抑制可能是该药抗癌作用的重要机制。因此，表现出高Survivin表达和表观遗传沉默的转化生长因子βRII的患者群体可能会从这种组蛋白去乙酰酶抑制剂的使用中受益。
Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor beta receptor II (TGF beta RII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGF beta signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGF beta signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGF beta/protein kinase A signaling pathway. Induction of TGF beta RII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGF beta RII might potentially benefit from the use of this histone deacetylase inhibitor.