Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation
By S. Haggarty, K. M. Koeller, Jason C. Wong, C. Grozinger, Stefan Schreiber. Proceedings of the National Academy of Sciences of the United States of America, 2003
1,098 citations recorded by the source corpus.
Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, chemical genetic screen of 7,392 small molecules was used to discover “tubacin,” which inhibits α-tubulin deacetylation in mammalian cells. Tubacin does not affect the level of histone acetylation, gene-expression patterns, or cell-cycle progression. We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin. Only one of the two catalytic domains of HDAC6 possesses tubulin deacetylase activity, and only this domain is bound by tubacin. Tubacin treatment did not affect the stability of microtubules but did decrease cell motility. HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules. Our results highlight the role of α-tubulin acetylation in mediating the localization of microtubule-associated proteins. They also suggest that small molecules that selectively inhibit HDAC6-mediated α-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a1777368ce1d2da3bfdacccadd8102f1989f7422
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Citations in the corpus
- New and emerging HDAC inhibitors for cancer treatment. (2014, background): “However, inhibiting HDAC6 with tubacin was not sufficient to induce cell death (82), as protein aggregates can be degraded by the proteaseome.”
- Histone deacetylase inhibitors: molecular mechanisms of action (2007, background): “A small molecule, tubacin, selectively inhibits HDAC6 activity and causes an accumulation of acetylated atubulin, but does not affect acetylation of histones, and does not inhibit cell cycle progression (Haggarty et al., 2003).”
- Microtubule acetylation promotes kinesin-1 binding and transport. (2006, methodology): “Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation.”
- HDAC6 modulates cell motility by altering the acetylation level of cortactin. (2007, background): “…IH -PA Author M anuscript Discussion Results from previous studies have shown that HDAC6 associates with and regulates the acetylation of α-tubulin and Hsp90 (Bali et al., 2005; Haggarty et al., 2003; Hubbert et al., 2002; Kovacs et al., 2005; Matsuyama et al., 2002; Zhang et al., 2003).”
- Histone Deacetylase Inhibitors: Potential in Cancer Therapy (2009, background): “A number of HDAC isoform selective or specific inhibitors are currently in development [Haggarty et al., 2003; Somoza et al., 2004; Kozikowski et al., 2007; Rasheed et al., 2007; Butler and Kozikowski, 2008; Estiu et al., 2008; Khan et al., 2008; Moradei et al., 2008; Jones et al., 2008a; Schemies e”
- Therapeutic application of histone deacetylase inhibitors for central nervous system disorders (2008, background): “Tubacin was identified as a class IIb HDAC6-specific inhibitor, and notably appears to be domain selectiv”
- ChemMine. A Compound Mining Database for Chemical Genomics1 (2005, background): “In analogy to genetic screens, chemical genomic screens can utilize forward and reverse strategies (Schreiber, 1998; Haggarty et al., 2003).”