Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

Kerr, E. et al. (2012) Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death and Differentiation, 19(8), pp. 1317-1327. (doi: 10.1038/cdd.2012.8)

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Abstract

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'.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Riley, Dr Joel
Authors: Kerr, E., Holohan, C., McLaughlin, K.M., Majkut, J., Dolan, S., Redmond, K., Riley, J., McLaughlin, K., Stasik, I., Crudden, M., Van Schaeybroeck, S., Fenning, C., O'Connor, R., Kiely, P., Sgobba, M., Haigh, D., Johnston, P.G., and Longley, D.B.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death and Differentiation
Publisher:Nature Publishing Group
ISSN:1350-9047
ISSN (Online):1476-5403
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