Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair

Steven Foster, J. H. Lee, M. L. Choy, L. Ngo, Paul A. Marks

Research output: Contribution to journalArticle

229 Citations (Scopus)
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Abstract

Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death.
Original languageEnglish
Pages (from-to)14639-14644
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number33
DOIs
Publication statusPublished - 17 Aug 2010

Bibliographical note

Freely available online through the PNAS open access option

Keywords

  • γH2AX
  • DNA repair proteins
  • Vorinostat
  • Histones

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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