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Farnesyltransferase, HDAC6 and Cellular Microtubules

Our recent work reveals an important role for FTase in the upstream regulation of HDAC6 activity [14]. We showed that FTase, HDAC6 and the microtubules are organized as a protein complex and that FTase is removed from this complex upon inactivation by an FTI. Stable knock-down of the FTase alpha subunit in cells phenocopied the pharmacological inhibition of FTase and increased the basal levels of tubulin acetylation. Interestingly, these cells were also more sensitive to taxane treatment alone, or in combination with an FTI. This last result suggests that patients with low levels of FTase might benefit from taxane-based chemotherapy.

1. Marcus, A. I., J. Zhou, et al. (2005). The synergistic combination of the farnesyl transferase inhibitor lonafatnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. Cancer Res 65(9): 3883-93.

2. Marcus, A. I., M. O'Brate A, et al. (2006). Farnesyltransferase inhibitors reverse taxane resistance. Cancer Res 66(17): 8838-46.

3. Hubbert, C., A. Guardiola, et al. (2002). "HDAC6 is a microtubule-associated deacetylase." Nature 417(6887): 455-8.

4. Matsuyama, A., T. Shimazu, et al. (2002). "In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation." Embo J 21(24): 6820-31.

5. Zhang, Y., N. Li, et al. (2003). "HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo." Embo J 22(5): 1168-79.

6. Bali, P., M. Pranpat, et al. (2005). "Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors." J Biol Chem 280(29): 26729-34.

7. Kovacs, J. J., P. J. Murphy, et al. (2005). "HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor." Mol Cell 18(5): 601-7.

8. Murphy, P. J., Y. Morishima, et al. (2005). "Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone." J Biol Chem 280(40): 33792-9.

9. Hook, S. S., A. Orian, et al. (2002). "Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes." Proc Natl Acad Sci U S A 99(21): 13425-30.

10. Kawaguchi, Y., J. J. Kovacs, et al. (2003). "The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress." Cell 115(6): 727-38.

11. Grozinger, C. M., C. A. Hassig, et al. (1999). "Three proteins define a class of human histone deacetylases related to yeast Hda1p." Proc Natl Acad Sci U S A 96(9): 4868-73.

12. Zou, H., Y. Wu, et al. (2006). "Characterization of the two catalytic domains in histone deacetylase 6." Biochem Biophys Res Commun 341(1): 45-50.

13. Haggarty, S. J., K. M. Koeller, et al. (2003). "Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation." Proc Natl Acad Sci U S A 100(8): 4389-94.

14. Zhou, J., C. Chanel Vos, et al. (2009). The protein Farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. J Biol Chem. 2009 Apr 10;284(15):9648-55. Epub 2009 Feb 18.