Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer.
Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer.
复制标题
DOI：
10.1002/ijc.28672
复制
发表时间：
2014-12-01
影响因子：
6.4
通讯作者：
Baba, H.
中科院分区：
文献类型：
--
作者：
Ishikawa, S.;Hayashi, H.;Kinoshita, K.;Abe, M.;Kuroki, H.;Tokunaga, R.;Tomiyasu, S.;Tanaka, H.;Sugita, H.;Arita, T.;Yagi, Y.;Watanabe, M.;Hirota, M.;Baba, H.
虽然他汀类药物摄入已被证明可以降低结直肠癌（CRC）的风险，但其抗肿瘤作用的机制和生存益处的临床意义仍不清楚。他汀类药物诱导的抗增殖作用和其潜在的机制进行了检查，使用六个CRC细胞系。尽管辛伐他汀和普伐他汀均能激活甲羟戊酸途径，但除普伐他汀外的他汀类药物均表现出抗增殖作用（辛伐他汀≥氟伐他汀>阿托伐他汀），提示他汀类药物的抗增殖作用依赖于非甲羟戊酸途径。事实上，他汀类药物通过下调组蛋白甲基转移酶增强子zeste同源物2（EZH2）诱导p27 KIP 1表达，EZH2作为表观遗传基因沉默子。此外，辛伐他汀加II类组蛋白脱乙酰酶（HDAC）抑制剂（MC1568）的使用通过抑制源自CRC细胞中下调的EZH2的HDAC 5诱导来诱导p27 KIP 1的进一步过表达，并且协同地导致相当大的抗增殖作用。在临床环境中，通过免疫组织化学染色，他汀类药物摄入（普伐他汀除外）显示在切除的CRC中下调EZH2表达和反向上调p27 KIP1表达，并且与未摄入他汀类药物的患者相比，导致总生存率（p = 0.02）和无病生存率（p < 0.01）的显著改善。他汀类药物可能通过EZH2介导的表观遗传改变抑制肿瘤进展，这导致切除CRC后的生存益处。此外，他汀类药物联合II类HDAC抑制剂可能是一种新的抗癌治疗CRC的协同效应。
While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin-induced antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin ≥ fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin-mediated antiproliferative effects depended on non-mevalonate pathway. Indeed, statin induced p27KIP1 expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27KIP1 by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27KIP1 expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2-mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC.
登录
查看更多内容
影响因子：
8.8
作者：
Kawata, S;Yamasaki, E;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
影响因子：
64.8
作者：
Varambally, S;Dhanasekaran, SM;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM
影响因子：
4.7
作者：
Wächtershäuser, A;Akoglu, B;Stein, J
通讯作者：
Stein, J
影响因子：
4.8
作者：
Sato, R;Inoue, J;Maeda, M
通讯作者：
Maeda, M
影响因子：
56.9
作者：
Cao, R;Wang, LJ;Zhang, Y
通讯作者：
Zhang, Y