期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 8, 页码 1317-1327出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2012.8
关键词
Ku70; FLIP; caspase 8; HDAC inhibitors; colorectal cancer; apoptosis
资金
- Cancer Research UK
- Department for Employment and Learning, NI
- MRC [G0900870, G0400302] Funding Source: UKRI
- Cancer Research UK [13172, 13721] Funding Source: researchfish
- Medical Research Council [G0900870, G0400302] Funding Source: researchfish
- Public Health Agency [RRG/3261/05] Funding Source: researchfish
FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-specific inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as efficient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as 'FLIP inhibitors'. Cell Death and Differentiation (2012) 19, 1317-1327; doi:10.1038/cdd.2012.8; published online 10 February 2012
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据