Determination of the Class and Isoform Selectivity of Small-Molecule Histone Deacetylase Inhibitors

Research Article | Biochemical Journal
Determination of the Class and Isoform Selectivity of Small-Molecule Histone Deacetylase Inhibitors
Author's Information

James W. Ritchie

Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.

Anthony Tumber

Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.

Laura S. Collins

Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.

Paul W. Finn

Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.

Nessa Carey

Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.

Stanny C. Berghs

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Evan Mills

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Xiaozhong Qian

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Nicholai Khramtsov

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Ferenc Boldog

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Craig Hackett

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Sampath Kumar

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Michael Jeffers

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Nagma Khan

Topotarget UK Ltd, 87a Milton Park, Abingdon, Oxon, OX14 4RY, U.K.

Peter Buhl Jensen

Topotarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark

Henri S. Lichenstein

CuraGen Corporation, 322 East Main Street, Branford, CT 06405, U.S.A.

Maxwell Sehested

Topotarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark
Abstract

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.

Keywords

deacetylation, histone deacetylase (HDAC), histone deacetylase isoforms (HDAC isoforms), small-molecule inhibitors, tubulin

DOI: 10.1042/BJ20070779

ADLID: 31178-v4

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Keywords
deacetylation histone deacetylase (HDAC) histone deacetylase isoforms (HDAC isoforms) small-molecule inhibitors tubulin

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