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

E Kerr1, C Holohan, K M McLaughlin

  • 1Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.

Cell Death and Differentiation
|February 11, 2012
PubMed

Insights

Histone deacetylase (HDAC) inhibitors like Vorinostat disrupt the FLIP/Ku70 complex, leading to FLIP degradation and apoptosis. This reveals HDAC inhibitors as potential anti-cancer drugs by targeting FLIP expression post-transcriptionally.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • FLIP (FLICE-inhibitory protein) is a target in anti-cancer therapy, inhibiting apoptosis by blocking caspase 8 activation.
  • FLIP stability is regulated by interactions with other proteins, influencing its therapeutic potential.

Purpose of the Study:

  • To investigate the novel interaction between FLIP and the DNA repair protein Ku70.
  • To determine the effect of histone deacetylase (HDAC) inhibitors on FLIP protein stability and apoptosis in colorectal cancer models.

Main Methods:

  • Investigated the FLIP/Ku70 interaction and its effect on FLIP polyubiquitination.
  • Utilized in vitro and in vivo colorectal cancer models to assess the impact of HDAC inhibitors (Vorinostat/SAHA, Tubacin).
  • Analyzed FLIP downregulation, caspase 8 activation, and apoptosis induction.

Main Results:

  • Identified a novel interaction between FLIP and Ku70, where Ku70 inhibits FLIP polyubiquitination, stabilizing FLIP.
  • Vorinostat (SAHA) treatment enhanced Ku70 acetylation, disrupting the FLIP/Ku70 complex and promoting FLIP polyubiquitination and proteasomal degradation.
  • SAHA-induced apoptosis in colorectal cancer models was dependent on FLIP downregulation and caspase 8 activation.
  • HDAC6 inhibition by Tubacin mimicked SAHA's effects, highlighting HDAC6's role in Ku70 acetylation and FLIP stability.

Conclusions:

  • HDAC inhibitors, particularly those targeting HDAC6, effectively suppress FLIP expression post-transcriptionally by destabilizing the FLIP/Ku70 complex.
  • These findings establish HDAC inhibitors as potential 'FLIP inhibitors' and viable therapeutic agents for colorectal cancer treatment.

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