Trichostatin A

Lipidomics Gateway (26 August 2009) [doi:10.1038/lipidmaps.2009.23]

Initially isolated from bacteria as an antifungal antibiotic, the linear polyketide Trichostatin A is a potent reversible inhibitor of histone deacetylases, with myriad applications.

Model of trichostatin A. Visit trichostatin in the LIPID MAPS database for more molecular information.

Trichostatin A (TSA) was first isolated in the 1970s in a screen for antifungal compounds from the soil bacterium Streptomyces hygroscopicus 1 but a wider potential was soon revealed. TSA can arrest the mammalian cell cycle, and induces differentiation of tumor cells, as shown in various studies during the 1980s. However, it was not until the end of the decade that TSA-treated cells were first found to have hyperacetylation of their histones, due to decreased deacetylation 2 . Now, TSA is known as a potent histone deacetylase (HDAC)-specific inhibitor 3 .

HDAC inhibition: TSA wears the HAT

The acetylation of histones neutralizes positive charges on their tail regions, reducing their ability to bind to DNA and thus loosening the structure of chromatin. Highly acetylated regions are more accessible to the transcription machinery and are actively transcribed. Whereas histone acetyltransferase (HAT) enzymes add acetyl groups, HDACs remove them, and the balance of these activities contributes to transcriptional control. By inhibiting HDAC action, TSA mimics HAT activity, leading to hyperacetylation of chromatin.

Mechanism: A taste for metal

In a co-crystallization study with a HDAC, TSA was found to coordinate a zinc cation from the enzyme active-site pocket, as well as contacting amino acids 4 . Effective against multiple classes of HDAC at just nanomolar concentrations, TSA is both potent and reversible.

Family background: Meet the polyketides

The synthesis of polyketides resembles fatty acid synthesis and involves polymerization of acetyl and propionyl subunits. These secondary metabolites are found in many organisms but the majority of isolated compounds derive from bacteria 5 . Whereas TSA is a linear polyketide, other classes include the polyether antibiotics (including monensin A) and the cytochalasins.

Functions: From biochemical tool to therapeutic agent

The use of inhibitors has greatly aided the study of the complicated interplay of HDAC and HAT function, although much remains to decipher. The potential to modulate these activities in vivo is now the focus of much research and targets include cancer, connective tissue disease, multiple sclerosis and other inflammatory and autoimmune conditions 6 7 8 . The inhibition of multiple HDAC isoforms by TSA could be problematic for its use in patients; however, the complete reversibility of its action presents the opportunity to halt any unwanted side effects. The authors of a recent study caution that these might include pro-atherogenic effects as TSA unexpectedly enhances vascular proliferative activity. Further research will determine whether TSA will prove directly useful in fighting disease, or only indirectly by helping to clarify HDAC functions 9 .

References:

  1. Tsuji, N. et al. A new antifungal antibiotic, Trichostatin.

    J. Antibiot. 29, 1-9 (1976).

  2. Yoshida, M. et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.

    J. Biol. Chem. 265, 17174-17179 (1990).

  3. Yoshida, M., Horinouchi, S. and Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function.

    Bioessays 17, 423-430 (1995).

  4. Vannini, A. et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor.

    Proc. Natl Acad. Sci. USA 101, 15064-15069 (2004). doi:10.1073/pnas.0404603101

  5. Robinson, J.A. Polyketide synthase complexes: their structure and function in antibiotic biosynthesis.

    Philos Trans R Soc Lond B Biol Sci 332, 107-114 (1991). doi:10.1098/rstb.1991.0038

  6. Mariadason, J.M. HDACs and HDAC inhibitors in colon cancer.

    Epigenetics 3, 28-37 (2008).

  7. Kazantsey, A.G. and Thompson, L.M. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders.

    Nat. Rev. Drug Discovery 7, 854-868 (2008). doi:10.1038/nrd2681

  8. Wang, L.W., Tao, R. and Hancock, W.W. Using histone deacetylase inhibitors to enhance Foxp3+ regulatory T-cell function and induce allograft tolerance.

    Immunol. Cell Biol. 87, 195-202 (2009). doi:10.1038/icb.2008.106

  9. Song, S.S., Kang, S.W. and Choi, C. Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1.

    Cardiovascular Res. (13 August 2009). doi:10.1093/cvr/cvp263