Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.

Research output: Contribution to journalArticle

Abstract

Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.

Details

Authors
  • Patrick Brest
  • Mattias Gustafsson
  • Anki Mossberg
  • Lotta Gustafsson
  • Caroline Düringer
  • Ali Hamiche
  • Catharina Svanborg
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Histone Deacetylases: metabolism, Histones: metabolism, Histone Deacetylases: antagonists & inhibitors, Hela Cells: drug effects, Enzyme Inhibitors: pharmacology, Cyclin-Dependent Kinase Inhibitor p21: metabolism, Chromatin: ultrastructure, Chromatin: metabolism, Chromatin: drug effects, Cell Survival: drug effects, Acetylation: drug effects, Oleic Acids: pharmacology, Lactalbumin: pharmacology, Jurkat Cells: drug effects, Hydroxamic Acids: pharmacology
Original languageEnglish
Pages (from-to)11327-11334
JournalCancer Research
Volume67
Issue number23
Publication statusPublished - 2007
Publication categoryResearch
Peer-reviewedYes