The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lys™ (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform.
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Research Article|
December 21 2007
Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors
Nagma Khan;
Nagma Khan
1
*Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.
1To whom correspondence should be addressed (e-mail nagmabkhan@yahoo.co.uk).
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Michael Jeffers;
Michael Jeffers
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Sampath Kumar;
Sampath Kumar
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Craig Hackett;
Craig Hackett
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Ferenc Boldog;
Ferenc Boldog
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Nicholai Khramtsov;
Nicholai Khramtsov
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Xiaozhong Qian;
Xiaozhong Qian
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Evan Mills;
Evan Mills
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Stanny C. Berghs;
Stanny C. Berghs
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Nessa Carey;
Nessa Carey
*Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.
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Paul W. Finn;
Paul W. Finn
*Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.
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Laura S. Collins;
Laura S. Collins
*Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.
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Anthony Tumber;
Anthony Tumber
*Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.
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James W. Ritchie;
James W. Ritchie
*Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.
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Peter Buhl Jensen;
Peter Buhl Jensen
†Topotarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark
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Henri S. Lichenstein;
Henri S. Lichenstein
‡CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.
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Maxwell Sehested
Maxwell Sehested
†Topotarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark
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Publisher: Portland Press Ltd
Received:
June 11 2007
Revision Received:
September 07 2007
Accepted:
September 14 2007
Accepted Manuscript online:
September 14 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 409 (2): 581–589.
Article history
Received:
June 11 2007
Revision Received:
September 07 2007
Accepted:
September 14 2007
Accepted Manuscript online:
September 14 2007
Citation
Nagma Khan, Michael Jeffers, Sampath Kumar, Craig Hackett, Ferenc Boldog, Nicholai Khramtsov, Xiaozhong Qian, Evan Mills, Stanny C. Berghs, Nessa Carey, Paul W. Finn, Laura S. Collins, Anthony Tumber, James W. Ritchie, Peter Buhl Jensen, Henri S. Lichenstein, Maxwell Sehested; Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 15 January 2008; 409 (2): 581–589. doi: https://doi.org/10.1042/BJ20070779
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