Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities

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

Research output: Contribution to journalArticle

33 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
Issue number12
DOIs
Publication statusPublished - Dec 2013

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Histone Deacetylase Inhibitors
Histones
Acetylation
Proteins
Chromatin Assembly and Disassembly
Caspases
Antineoplastic Agents
Neoplasms
vorinostat
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Newbold, A., Matthews, G. M., Bots, M., Cluse, L. A., Clarke, C. J. P., Banks, K. M., ... Johnstone, R. W. (2013). Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities. Molecular Cancer Therapeutics, 12(12), 2709-2721. https://doi.org/10.1158/1535-7163.MCT-13-0626

Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities. / Newbold, Andrea; Matthews, Geoffrey M.; Bots, Michael; Cluse, Leonie A.; Clarke, Christopher J P; Banks, Kellie Marie; Cullinane, Carleen; Bolden, Jessica E.; Christiansen, Ailsa J.; Dickins, Ross A.; Miccolo, Claudia; Chiocca, Susanna; Kral, Astrid M.; Ozerova, Nicole D.; Miller, Thomas A.; Methot, Joey L.; Richon, Victoria M.; Secrist, J. Paul; Minucci, Saverio; Johnstone, Ricky W.

In: Molecular Cancer Therapeutics, Vol. 12, No. 12, 12.2013, p. 2709-2721.

Research output: Contribution to journalArticle

Newbold, A, Matthews, GM, Bots, M, Cluse, LA, Clarke, CJP, Banks, KM, Cullinane, C, Bolden, JE, Christiansen, AJ, Dickins, RA, Miccolo, C, Chiocca, S, Kral, AM, Ozerova, ND, Miller, TA, Methot, JL, Richon, VM, Secrist, JP, Minucci, S & Johnstone, RW 2013, 'Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities', Molecular Cancer Therapeutics, vol. 12, no. 12, pp. 2709-2721. https://doi.org/10.1158/1535-7163.MCT-13-0626
Newbold, Andrea ; Matthews, Geoffrey M. ; Bots, Michael ; Cluse, Leonie A. ; Clarke, Christopher J P ; Banks, Kellie Marie ; Cullinane, Carleen ; Bolden, Jessica E. ; Christiansen, Ailsa J. ; Dickins, Ross A. ; Miccolo, Claudia ; Chiocca, Susanna ; Kral, Astrid M. ; Ozerova, Nicole D. ; Miller, Thomas A. ; Methot, Joey L. ; Richon, Victoria M. ; Secrist, J. Paul ; Minucci, Saverio ; Johnstone, Ricky W. / Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 12. pp. 2709-2721.
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