Domain-Selective Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6)-Mediated Tubulin Deacetylation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 8; pp. 4389 - 4394
• Main Authors: Haggarty, Stephen J., Koeller, Kathryn M., Wong, Jason C., Grozinger, Christina M., Schreiber, Stuart L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15-04-2003; National Acad Sciences; The National Academy of Sciences
• Subjects: 3T3 Cells; Acetylation; Anilides - pharmacology; Animals; Antibodies; Biological Sciences; Cell Cycle - drug effects; Cell Line; Cellular biology; Chemistry; Dioxanes - pharmacology; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; Enzymes; Gene Expression - drug effects; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases - chemistry; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Humans; Hydroxamic Acids - pharmacology; Jurkat Cells; Mice; Microtubule-Associated Proteins - metabolism; Microtubules; Microtubules - drug effects; Molecules; NIH 3T3 cells; Physical Sciences; Protein Structure, Tertiary; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Stem cells; T lymphocytes; Tubulin - chemistry; Tubulin - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0430973100

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.