Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis.
Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis.
复制标题
DOI：
10.1016/j.molcel.2008.09.011
复制
发表时间：
2008-10-10
期刊：
影响因子：
16
通讯作者：
Deng, Chu-Xia
中科院分区：
文献类型：
--
作者：
Wang, Rui-Hong;Zheng, Yin;Kim, Hyun-Seok;Xu, Xiaoling;Cao, Liu;Luhasen, Tyler;Lee, Mi-Hye;Xiao, Cuiying;Vassilopoulos, Athanassios;Chen, Weiping;Gardner, Kevin;Man, Yan-Gao;Hung, Mien-Chie;Finkel, Toren;Deng, Chu-Xia
BRCA1的生殖系突变使妇女易患乳腺癌和卵巢癌。然而，BRCA1在肿瘤抑制中的下游介质仍然难以捉摸。我们发现人类BRCA1相关乳腺癌的SIRT1水平低于正常对照。我们进一步证明了BRCA1突变小鼠的乳腺肿瘤具有低水平的SIRT1和高水平的Survivin，这可以通过BRCA1的诱导表达来逆转。BRCA1与SIRT1启动子结合并增加SIRT1表达，这反过来又通过改变组蛋白H3的表观遗传修饰来抑制Survivin。SIRT1的缺失阻断了BRCA1对Survivin的调节。此外，我们证明了白藜芦醇对SIRT1的激活和Survivin表达的抑制在体外和体内对BRCA1突变型癌细胞比对BRCA1野生型癌细胞引起更深刻的抑制作用。这些研究结果表明，白藜芦醇治疗是BRCA1相关乳腺癌靶向治疗的一个很好的策略。
Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from BRCA1 mutant mice have low levels of SIRT1 and high levels of Survivin, which is reversed by induced expression of BRCA1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of SIRT1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on BRCA1-mutant cancer cells than on BRCA1-wild type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.
登录
查看更多内容
影响因子：
14.9
作者：
Coumoul, X;Li, WM;Deng, CX
通讯作者：
Deng, CX
影响因子：
20.3
作者：
Estrov, Z;Shishodia, S;Aggarwal, BB
通讯作者：
Aggarwal, BB
影响因子：
8
作者：
Brodie, SG;Xu, XL;Deng, CX
通讯作者：
Deng, CX
影响因子：
64.8
作者：
Baur, Joseph A.;Pearson, Kevin J.;Sinclair, David A.
通讯作者：
Sinclair, David A.
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME