Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities

Andrea Newbold, Geoffrey Mark Matthews, Michael Bots, Leonie A Cluse, Christopher J P Clarke, Kellie-Marie Banks, Carleen M Cullinane, Jessica E Bolden, Ailsa Jane Christiansen, Ross Alexander Dickins, Claudia Miccolo, Susanna Chiocca, Astrid M Kral, Nicole D Ozerova, Thomas A Miller, Joey L Methot, V M Richon, Jack Paul Secrist, Saverio Minucci, Ricky W Johnstone

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36 Citations (Scopus)

Abstract

Histone deacetylase inhibitors (HDACi) are anticancer agents that induce hyperacetylation of histones, resulting in chromatin remodeling and transcriptional changes. In addition, nonhistone proteins, such as the chaperone protein Hsp90, are functionally regulated through hyperacetylation mediated by HDACis. Histone acetylation is thought to be primarily regulated by HDACs 1, 2, and 3, whereas the acetylation of Hsp90 has been proposed to be specifically regulated through HDAC6. We compared the molecular and biologic effects induced by an HDACi with broad HDAC specificity (vorinostat) with agents that predominantly inhibited selected class I HDACs (MRLB-223 and romidepsin). MRLB-223, a potent inhibitor of HDACs 1 and 2, killed tumor cells using the same apoptotic pathways as the HDAC 1, 2, 3, 6, and 8 inhibitor vorinostat. However, vorinostat induced histone hyperacetylation and killed tumor cells more rapidly than MRLB-223 and had greater therapeutic efficacy in vivo. FDCP-1 cells dependent on the Hsp90 client protein Bcr-Abl for survival, were killed by all HDACis tested, concomitant with caspase-dependent degradation of Bcr-Abl. These studies provide evidence that inhibition of HDAC6 and degradation of Bcr-Abl following hyperacetylation of Hsp90 is likely not a major mechanism of action of HDACis as had been previously posited
Original languageEnglish
Pages (from-to)2709 - 2721
Number of pages13
JournalMolecular Cancer Therapeutics
Volume12
DOIs
Publication statusPublished - 2013
Externally publishedYes

Cite this

Newbold, A., Matthews, G. M., Bots, M., Cluse, L. A., Clarke, C. J. P., Banks, K-M., Cullinane, C. M., Bolden, J. E., Christiansen, A. J., Dickins, R. A., Miccolo, C., Chiocca, S., Kral, A. M., Ozerova, N. D., Miller, T. A., Methot, J. L., Richon, V. M., Secrist, J. P., Minucci, S., & Johnstone, R. W. (2013). Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities. Molecular Cancer Therapeutics, 12, 2709 - 2721. https://doi.org/10.1158/1535-7163.MCT-13-0626