SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis.
SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis.
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DOI：
10.1038/cdd.2011.71
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发表时间：
2011-12
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
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突变型p53癌症的生存令人惊讶地依赖于其超稳定的mutp 53蛋白，将mutp 53鉴定为潜在的重要临床靶点。然而，针对mutp 53的有效小分子疗法的探索才刚刚开始。Mutp 53超稳定是p53突变的标志，是癌细胞特异性的，并且是由于恶性转化期间HSP 90伴侣机制的大量上调。我们最近发现，热休克蛋白90和它的mutp 53客户端之间的稳定复合物的形成抑制E3连接酶MDM 2和CHIP，导致mutp 53稳定。HDAC抑制剂（HDACi）是一类新的有前途的抗肿瘤药物，其作用靶点是使组蛋白和非组蛋白过乙酰化。目前，SAHA是唯一获得FDA批准的HDACi。我们发现，SAHA表现出优先的突变体，而不是野生型和空p53人癌细胞的细胞毒性。功能丧失/获得实验表明，尽管能够发挥多种细胞效应，但SAHA的细胞毒性在很大程度上是由其在蛋白质降解水平上强烈破坏mutp 53稳定性的能力引起的。潜在的机制是SAHA对HDAC 6的抑制，HDAC 6是HSP 90的重要正调节剂。这释放了mutp 53，并使其能够被MDM 2和CHIP介导的降解。SAHA还由于其降解mutp 53的能力而使mutp 53癌细胞对化疗强烈化学增敏。这确定了SAHA的一种新作用，其前景是SAHA成为mutp 53特异性抗癌策略的核心。
Mutant p53 cancers are surprisingly dependent on their hyperstable mutp53 protein for survival, identifying mutp53 as a potentially significant clinical target. However, exploration of effective small molecule therapies targeting mutp53 has barely begun. Mutp53 hyperstabilization, a hallmark of p53 mutation, is cancer cell-specific and due to massive upregulation of the HSP90 chaperone machinery during malignant transformation. We recently showed that stable complex formation between HSP90 and its mutp53 client inhibits E3 ligases MDM2 and CHIP, causing mutp53 stabilization. HDAC inhibitors (HDACi) are a new class of promising anti-cancer drugs, hyperacetylating histone and non-histone targets. Currently, SAHA is the only FDA-approved HDACi. We show that SAHA exhibits preferential cytotoxicity for mutant, rather than wildtype and null p53 human cancer cells. Loss/gain-of-function experiments revealed that although able to exert multiple cellular effects, SAHA's cytotoxicity is caused to a significant degree by its ability to strongly destabilize mutp53 at the level of protein degradation. The underlying mechanism is SAHA's inhibition of HDAC6, an essential positive regulator of HSP90. This releases mutp53 and enables its MDM2- and CHIP-mediated degradation. SAHA also strongly chemosensitizes mutp53 cancer cells for chemotherapy due to its ability to degrade mutp53. This identifies a novel action of SAHA with the prospect of SAHA becoming a centerpiece in mutp53-specific anticancer strategies.
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影响因子：
5.3
作者：
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通讯作者：
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