Histone deacetylase inhibitors (HDI) cause DNA damage in leukemia cells: a mechanism for leukemia-specific HDI-dependent apoptosis?

TJ Gaymes, RA Padua, M Pla, S Orr, N Omidvar, C Chomienne, GJ Mufti, FV Rassool

    Research output: Contribution to journalArticlepeer-review

    92 Citations (Scopus)

    Abstract

    Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events determine the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis.
    Original languageEnglish
    Pages (from-to)563 - 573
    Number of pages11
    JournalMOLECULAR CANCER RESEARCH
    Volume4
    Issue number8
    DOIs
    Publication statusPublished - Aug 2006

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