A Novel Sirtuin 2 ( SIRT2) Inhibitor with p53-dependent Pro- apoptotic Activity in Non- small Cell Lung Cancer*
A Novel Sirtuin 2 ( SIRT2) Inhibitor with p53-dependent Pro- apoptotic Activity in Non- small Cell Lung Cancer*
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DOI：
10.1074/jbc.m113.487736
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发表时间：
2014-02-21
影响因子：
4.8
通讯作者：
Ehrenhofer-Murray, Ann E.
中科院分区：
文献类型：
--
作者：
Hoffmann, Gesine;Breitenbuecher, Frank;Ehrenhofer-Murray, Ann E.
背景：NAD(+) 依赖性脱乙酰酶 SIRT2 的药理学抑制通过防止 p53 的脱乙酰化和失活而有望用于癌症治疗。结果：我们鉴定了两种新型 SIRT2 抑制剂，它们以 p53 依赖性方式诱导细胞凋亡并激活三个 p53 靶基因。结论：SIRT2 的小分子抑制可激活癌细胞中 p53 依赖性细胞凋亡。意义：本文报道的化合物是用于癌症治疗的有前途的主要候选化合物。Sirtuin 2 (SIRT2) 是一种 NAD(+) 依赖性蛋白脱乙酰酶，其靶标包括组蛋白 H4 赖氨酸 16、p53 和 -微管蛋白。由于 p53 的脱乙酰化调节其对细胞凋亡的影响，因此药物抑制 SIRT2 依赖性 p53 脱乙酰化对于癌症的治疗具有重大的治疗意义。在这里，我们鉴定了两种结构相关的化合物，AEM1和AEM2，它们是SIRT2的选择性抑制剂（IC50值分别为18.5和3.8 m），但对其他sirtuins如SIRT1、SIRT3和酵母Sir2仅表现出微弱的作用。有趣的是，这两种化合物都能使非小细胞肺癌细胞系对 DNA 损伤剂依托泊苷诱导细胞凋亡变得敏感。重要的是，这种敏化依赖于功能性 p53 的存在，从而在这些化合物的 SIRT2 抑制与 p53 激活之间建立了联系。此外，AEM1 和 AEM2 处理导致 p53 乙酰化水平升高，CDKN1A 表达增加，CDKN1A 编码细胞周期调节因子 p21 (WAF1)，以及促凋亡基因 PUMA 和 NOXA（p53 的三个转录靶标）。总而言之，我们的数据表明，这些化合物对 SIRT2 的抑制通过减少 SIRT2 依赖性 p53 脱乙酰化而导致 p53 活化增加。因此，这些化合物为针对 p53 丰富的癌症的先导化合物优化和药物开发提供了良好的机会。
Background: Pharmacological inhibition of the NAD(+)-dependent deacetylase SIRT2 holds promise for cancer therapy by preventing deacetylation and inactivation of p53. Results: We identified two novel SIRT2 inhibitors that induce apoptosis in a p53-dependent fashion and activate three p53 target genes. Conclusion: Small-molecule inhibition of SIRT2 activates p53-dependent apoptosis in cancer cells. Significance: The compounds reported here are promising lead candidates for use in cancer treatment.Sirtuin 2 (SIRT2) is an NAD(+)-dependent protein deacetylase whose targets include histone H4 lysine 16, p53, and -tubulin. Because deacetylation of p53 regulates its effect on apoptosis, pharmacological inhibition of SIRT2-dependent p53 deacetylation is of great therapeutic interest for the treatment of cancer. Here, we have identified two structurally related compounds, AEM1 and AEM2, which are selective inhibitors of SIRT2 (IC50 values of 18.5 and 3.8 m, respectively), but show only weak effects on other sirtuins such as SIRT1, SIRT3, and yeast Sir2. Interestingly, both compounds sensitized non-small cell lung cancer cell lines toward the induction of apoptosis by the DNA-damaging agent etoposide. Importantly, this sensitization was dependent on the presence of functional p53, thus establishing a link between SIRT2 inhibition by these compounds and p53 activation. Further, treatment with AEM1 and AEM2 led to elevated levels of p53 acetylation and to increased expression of CDKN1A, which encodes the cell cycle regulator p21(WAF1), as well as the pro-apoptotic genes PUMA and NOXA, three transcriptional targets of p53. Altogether, our data suggest that inhibition of SIRT2 by these compounds causes increased activation of p53 by decreasing SIRT2-dependent p53 deacetylation. These compounds thus provide a good opportunity for lead optimization and drug development to target p53-proficient cancers.