Differential effects of sulforaphane and related isothiocyanates on HDAC turnover and the DNA damage response in colon cancer cells Conference Paper uri icon

abstract

  • Abstract Protein acetylation is mediated by histone deacetylases (HDACs) and acetyltransferases, which influence chromatin dynamics, protein turnover, and the DNA damage response. HDACs overexpressed in cancer cells have been implicated in protecting against genotoxic insults, whereas HDAC inhibitors circumvent this protection (Rajendran et al. Clin Epigenetics 2011,3:4). Here, we show in human colon cancer cells that sulforaphane and related isothiocyanates (ITCs) inhibited HDAC activity and increased HDAC protein turnover, with the potency directly proportional to alkyl chain length. Under these conditions, DNA damage signaling was triggered by ATR kinases, leading to increased double-strand breaks and histone (H2AX) phosphorylation. Activation of checkpoint kinase-2 was followed by growth arrest and cell death. HDAC inhibition by ITCs enhanced the acetylation of repair proteins, like CtIP, leading to their degradation. Notably, cancer cells were more susceptible than normal cells, the latter exhibiting efficient double-strand-break processing and repair. Thus, dietary ITCs preferentially exploit the HDAC turnover pathways, faulty DNA repair mechanisms, and genomic instability in cancer cells. Supported by NIH grants CA090890, CA65525, CA122906, CA122959, CA80176, and ES007060. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-184. doi:1538-7445.AM2012-LB-184

published proceedings

  • CANCER RESEARCH

author list (cited authors)

  • Rajendran, P., Kidane, A. I., Yu, T., Dashwood, W., Ho, E., Williams, D. E., & Dashwood, R. H.

citation count

  • 0

complete list of authors

  • Rajendran, Praveen||Kidane, Ariam I||Yu, Tian-Wei||Dashwood, Wan-Mohaiza||Ho, Emily||Williams, David E||Dashwood, Roderick H

publication date

  • April 2012