Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation

Stephen J. Haggarty, Kathryn M. Koeller, Jason C. Wong, Christina M. Grozinger, Stuart L. Schreiber

Research output: Contribution to journalArticle

783 Citations (Scopus)

Abstract

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 a-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.

Original languageEnglish (US)
Pages (from-to)4389-4394
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number8
DOIs
StatePublished - Apr 15 2003

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Histone Deacetylase Inhibitors
Tubulin
Acetylation
Histone Deacetylases
Microtubules
Histones
Angiogenesis Inhibitors
Microtubule-Associated Proteins
Protein Binding
Cell Movement
tubacin
Catalytic Domain
Cell Cycle
Clinical Trials
Gene Expression
Research
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation",
abstract = "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 a-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.",
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Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. / Haggarty, Stephen J.; Koeller, Kathryn M.; Wong, Jason C.; Grozinger, Christina M.; Schreiber, Stuart L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 8, 15.04.2003, p. 4389-4394.

Research output: Contribution to journalArticle

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AU - Schreiber, Stuart L.

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