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

E Kerr, C Holohan, KM McLaughlin, J. Majkut, S Dolan, K Redmond, Joel Riley, K. McLaughlin, I Stasik, M. Crudden, S Van Schaeybroeck, C Fenning, R. O'Connor, P. Kiely, M Sgobba, D Haigh, PG Johnston, DB Longley

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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-speci?c 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 ef?cient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as ‘FLIP inhibitors’ © 2012 Macmillan Publishers Limited.
Original languageEnglish
Article numbere1745
Pages (from-to)1317-1327
Number of pages11
JournalCell Death and Differentiation
Volume19
Issue number8
DOIs
Publication statusPublished - Aug 2012

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Kerr, E., Holohan, C., McLaughlin, KM., 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, PG., & Longley, DB. (2012). Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death and Differentiation, 19(8), 1317-1327. [e1745]. https://doi.org/10.1038/cdd.2012.8