The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease

Clinical Science

Volumn 130, Issue 12, 2016, Pages 987-1003

  Batchu, Sri N ^a   Brijmohan, Angela S ^a   Advani, Andrew ^a  

^a ST MICHAEL'S HOSPITAL   (Canada)

Author keywords

Aggresome; Cancer; Histone deacetylase 6 (HDAC6); Misfolded protein response; Neurodegenerative disease; Proteasome

Indexed keywords

HISTONE DEACETYLASE 6; HISTONE DEACETYLASE INHIBITOR; LYSINE; HDAC6 PROTEIN, HUMAN; HISTONE DEACETYLASE;

ALZHEIMER DISEASE; CARDIOVASCULAR SYSTEM; CHRONIC DISEASE; ENZYME SUBSTRATE; HEREDITARY MOTOR SENSORY NEUROPATHY; HUMAN; HUNTINGTON CHOREA; INFLAMMATION; KIDNEY DISEASE; MALIGNANT NEOPLASTIC DISEASE; MOOD DISORDER; NONHUMAN; PARKINSON DISEASE; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN FOLDING; REVIEW; DRUG EFFECTS; METABOLISM; NEOPLASMS; NEURODEGENERATIVE DISEASES;

CHRONIC DISEASE; HISTONE DEACETYLASE INHIBITORS; HISTONE DEACETYLASES; HUMANS; NEOPLASMS; NEURODEGENERATIVE DISEASES;

EID: 84973547845     PISSN: 01435221     EISSN: 14708736     Source Type: Journal    
DOI: 10.1042/CS20160084     Document Type: Review

References (177)

1. Olsen, J.V., Blagoev, B., Gnad, F., Macek, B., Kumar, C., Mortensen, P. and Mann, M. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635-648
2. Polevoda, B. and Sherman, F. (2000) Nalpha-terminal acetylation of eukaryotic proteins. J. Biol. Chem. 275, 36479-36482
3. Brown, C.E., Lechner, T., Howe, L. and Workman, J.L. (2000) The many HATs of transcription coactivators. Trends Biochem. Sci. 25, 15-19
4. Marmorstein, R. and Roth, S.Y. (2001) Histone acetyltransferases: function, structure, and catalysis. Curr. Opin. Genet. Dev. 11, 155-161
5. Narlikar, G.J., Fan, H.Y. and Kingston, R.E. (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475-487
6. Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L., Rehman, M., Walther, T.C., Olsen, J.V. and Mann, M. (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834-840
7. Kouzarides, T. (2007) Chromatin modifications and their function. Cell 128, 693-705
8. Dhalluin, C., Carlson, J.E., Zeng, L., He, C., Aggarwal, A.K. and Zhou, M.M. (1999) Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491-496
9. Butler, K.V., Kalin, J., Brochier, C., Vistoli, G., Langley, B. and Kozikowski, A.P. (2010) Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J. Am. Chem. Soc. 132, 10842-10846
10. Rousseaux, S. and Khochbin, S. (2015) Histone acylation beyond acetylation: terra incognita in chromatin biology. Cell J. 17, 1-6
11. Chen, Y., Sprung, R., Tang, Y., Ball, H., Sangras, B., Kim, S.C., Falck, J.R., Peng, J., Gu, W. and Zhao, Y. (2007) Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell. Proteomics 6, 812-819
12. Tan, M., Luo, H., Lee, S., Jin, F., Yang, J.S., Montellier, E., Buchou, T., Cheng, Z., Rousseaux, S., Rajagopal, N. et al. (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016-1028
13. Dai, L., Peng, C., Montellier, E., Lu, Z., Chen, Y., Ishii, H., Debernardi, A., Buchou, T., Rousseaux, S., Jin, F. et al. (2014) Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat. Chem. Biol. 10, 365-370
14. Tan, M., Peng, C., Anderson, K.A., Chhoy, P., Xie, Z., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y. et al. (2014) Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 19, 605-617
15. Xie, Z., Dai, J., Dai, L., Tan, M., Cheng, Z., Wu, Y., Boeke, J.D. and Zhao, Y. (2012) Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100-107
16. Madsen, A.S. and Olsen, C.A. (2012) Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew. Chem. Int. Ed. Engl. 51, 9083-9087
17. Bao, X., Wang, Y., Li, X., Li, X.M., Liu, Z., Yang, T., Wong, C.F., Zhang, J., Hao, Q. and Li, X.D. (2014) Identification of 'erasers' for lysine crotonylated histone marks using a chemical proteomics approach. Elife 3, e02999
18. Liu, B., Lin, Y., Darwanto, A., Song, X., Xu, G. and Zhang, K. (2009) Identification and characterization of propionylation at histone H3 lysine 23 in mammalian cells. J. Biol. Chem. 284, 32288-32295
19. Grozinger, C.M., Hassig, C.A. and Schreiber, S.L. (1999) Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl. Acad. Sci. U.S.A. 96, 4868-4873
20. Verdel, A. and Khochbin, S. (1999) Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation-dependent chromatin modifiers. J. Biol. Chem. 274, 2440-2445
21. Voelter-Mahlknecht, S. and Mahlknecht, U. (2003) Cloning and structural characterization of the human histone deacetylase 6 gene. Int. J. Mol. Med. 12, 87-93
22. Verdel, A., Curtet, S., Brocard, M.P., Rousseaux, S., Lemercier, C., Yoshida, M. and Khochbin, S. (2000) Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr. Biol. 10, 747-749
23. Bertos, N.R., Gilquin, B., Chan, G.K., Yen, T.J., Khochbin, S. and and Yang, X.J. (2004) Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J. Biol. Chem. 279, 48246-48254
24. Han, Y., Jeong, H.M., Jin, Y.H., Kim, Y.J., Jeong, H.G., Yeo, C.Y. and Lee, K.Y. (2009) Acetylation of histone deacetylase 6 by p300 attenuates its deacetylase activity. Biochem. Biophys. Res. Commun. 383, 88-92
25. Liu, Y., Peng, L., Seto, E., Huang, S. and Qiu, Y. (2012) Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation. J. Biol. Chem. 287, 29168-29174
26. Kawaguchi, Y., Kovacs, J.J., McLaurin, A., Vance, J.M., Ito, A. and Yao, T.P. (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727-738
27. Seigneurin-Berny, D., Verdel, A., Curtet, S., Lemercier, C., Garin, J., Rousseaux, S. and Khochbin, S. (2001) Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol. Cell. Biol. 21, 8035-8044
28. Uhlen, M., Fagerberg, L., Hallstrom, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjostedt, E., Asplund, A. et al. (2015) Proteomics. Tissue-based map of the human proteome. Science 347, 1260419
29. Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.F. and Yao, T.P. (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417, 455-458
30. Zhang, Y., Li, N., Caron, C., Matthias, G., Hess, D., Khochbin, S. and Matthias, P. (2003) HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J. 22, 1168-1179
31. Matsuyama, A., Shimazu, T., Sumida, Y., Saito, A., Yoshimatsu, Y., Seigneurin-Berny, D., Osada, H., Komatsu, Y., Nishino, N., Khochbin, S. et al. (2002) In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 21, 6820-6831
32. Akella, J.S., Wloga, D., Kim, J., Starostina, N.G., Lyons-Abbott, S., Morrissette, N.S., Dougan, S.T., Kipreos, E.T. and Gaertig, J. (2010) MEC-17 is an alpha-tubulin acetyltransferase. Nature 467, 218-222
33. Shida, T., Cueva, J.G., Xu, Z., Goodman, M.B. and Nachury, M.V. (2010) The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc. Natl. Acad. Sci. U.S.A. 107, 21517-21522
34. North, B.J., Marshall, B.L., Borra, M.T., Denu, J.M. and Verdin, E. (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437-444
35. Maxwell, M.M., Tomkinson, E.M., Nobles, J., Wizeman, J.W., Amore, A.M., Quinti, L., Chopra, V., Hersch, S.M. and Kazantsev, A.G. (2011) The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS. Hum. Mol. Genet. 20, 3986-3996
36. Zhang, X., Yuan, Z., Zhang, Y., Yong, S., Salas-Burgos, A., Koomen, J., Olashaw, N., Parsons, J.T., Yang, X.J., Dent, S.R. et al. (2007) HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol. Cell 27, 197-213
37. Kovacs, J.J., Murphy, P.J., Gaillard, S., Zhao, X., Wu, J.T., Nicchitta, C.V., Yoshida, M., Toft, D.O., Pratt, W.B. and Yao, T.P. (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601-607
38. Parmigiani, R.B., Xu, W.S., Venta-Perez, G., Erdjument-Bromage, H., Yaneva, M., Tempst, P. and Marks, P.A. (2008) HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc. Natl. Acad. Sci. U.S.A. 105, 9633-9638
39. Mortenson, J.B., Heppler, L.N., Banks, C.J., Weerasekara, V.K., Whited, M.D., Piccolo, S.R., Johnson, W.E., Thompson, J.W. and Andersen, J.L. (2015) Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3zeta via deacetylation of lysines within the 14-3-3zeta binding pocket. J. Biol. Chem. 290, 12487-12496
40. Zhang, L., Liu, S., Liu, N., Zhang, Y., Liu, M., Li, D., Seto, E., Yao, T.P., Shui, W. and Zhou, J. (2015) Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity. Protein Cell 6, 42-54
41. Westendorf, J.J., Zaidi, S.K., Cascino, J.E., Kahler, R., van Wijnen, A.J., Lian, J.B., Yoshida, M., Stein, G.S. and Li, X. (2002) Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol. Cell. Biol. 22, 7982-7992
42. Zhang, W. and Kone, B.C. (2002) NF-kappaB inhibits transcription of the H(+)-K(+)-ATPase alpha(2)-subunit gene: role of histone deacetylases. Am. J. Physiol. Renal. Physiol. 283, F904-F911
43. Fernandes, I., Bastien, Y., Wai, T., Nygard, K., Lin, R., Cormier, O., Lee, H.S., Eng, F., Bertos, N.R., Pelletier, N. et al. (2003) Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and-independent mechanisms. Mol. Cell 11, 139-150
44. Palijan, A., Fernandes, I., Bastien, Y., Tang, L., Verway, M., Kourelis, M., Tavera-Mendoza, L.E., Li, Z., Bourdeau, V., Mader, S. et al. (2009) Function of histone deacetylase 6 as a cofactor of nuclear receptor coregulator LCoR. J. Biol. Chem. 284, 30264-30274
45. Lagger, G., O'Carroll, D., Rembold, M., Khier, H., Tischler, J., Weitzer, G., Schuettengruber, B., Hauser, C., Brunmeir, R., Jenuwein, T. and Seiser, C. (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21, 2672-2681
46. Montgomery, R.L., Davis, C.A., Potthoff, M.J., Haberland, M., Fielitz, J., Qi, X., Hill, J.A., Richardson, J.A. and Olson, E.N. (2007) Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21, 1790-1802
47. Montgomery, R.L., Potthoff, M.J., Haberland, M., Qi, X., Matsuzaki, S., Humphries, K.M., Richardson, J.A., Bassel-Duby, R. and Olson, E.N. (2008) Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J. Clin. Invest. 118, 3588-3597
48. Vega, R.B., Matsuda, K., Oh, J., Barbosa, A.C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J.M., Richardson, J.A. et al. (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119, 555-566
49. Chang, S., Young, B.D., Li, S., Qi, X., Richardson, J.A. and Olson, E.N. (2006) Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126, 321-334
50. Haberland, M., Mokalled, M.H., Montgomery, R.L. and Olson, E.N. (2009) Epigenetic control of skull morphogenesis by histone deacetylase 8. Genes Dev. 23, 1625-1630
51. Zhang, Y., Kwon, S., Yamaguchi, T., Cubizolles, F., Rousseaux, S., Kneissel, M., Cao, C., Li, N., Cheng, H.L., Chua, K. et al. (2008) Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell Biol. 28, 1688-1701
52. Song, Y. and Brady, S.T. (2015) Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol 25, 125-136
53. Howes, S.C., Alushin, G.M., Shida, T., Nachury, M.V. and Nogales, E. (2014) Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure. Mol. Biol. Cell 25, 257-266
54. Boyault, C., Zhang, Y., Fritah, S., Caron, C., Gilquin, B., Kwon, S.H., Garrido, C., Yao, T.P., Vourc'h, C., Matthias, P. and Khochbin, S. (2007) HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 21, 2172-2181
55. Schubert, U., Anton, L.C., Gibbs, J., Norbury, C.C., Yewdell, J.W. and Bennink, J.R. (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770-774
56. Yan, J. (2014) Interplay between HDAC6 and its interacting partners: essential roles in the aggresome-autophagy pathway and neurodegenerative diseases. DNA Cell Biol. 33, 567-580
57. Corboy, M.J., Thomas, P.J. and Wigley, W.C. (2005) Aggresome formation. Methods Mol. Biol. 301, 305-327
58. Kopito, R.R. (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10, 524-530
59. Johnston, J.A., Illing, M.E. and Kopito, R.R. (2002) Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. Cell Motil. Cytoskeleton 53, 26-38
60. Boyault, C., Gilquin, B., Zhang, Y., Rybin, V., Garman, E., Meyer-Klaucke, W., Matthias, P., Muller, C.W. and Khochbin, S. (2006) HDAC6-p97/VCP controlled polyubiquitin chain turnover. EMBO J. 25, 3357-3366
61. Meyer, H., Bug, M. and Bremer, S. (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14, 117-123
62. Lee, J.Y., Koga, H., Kawaguchi, Y., Tang, W., Wong, E., Gao, Y.S., Pandey, U.B., Kaushik, S., Tresse, E., Lu, J. et al. (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 29, 969-980
63. Olsen, E.A., Kim, Y.H., Kuzel, T.M., Pacheco, T.R., Foss, F.M., Parker, S., Frankel, S.R., Chen, C., Ricker, J.L., Arduino, J.M. and Duvic, M. (2007) Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25, 3109-3115
64. Piekarz, R.L., Frye, R., Turner, M., Wright, J.J., Allen, S.L., Kirschbaum, M.H., Zain, J., Prince, H.M., Leonard, J.P., Geskin, L.J. et al. (2009) Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J. Clin. Oncol. 27, 5410-5417
65. Foss, F., Advani, R., Duvic, M., Hymes, K.B., Intragumtornchai, T., Lekhakula, A., Shpilberg, O., Lerner, A., Belt, R.J., Jacobsen, E.D. et al. (2015) A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br. J. Haematol. 168, 811-819
66. Richardson, P.G., Schlossman, R.L., Alsina, M., Weber, D.M., Coutre, S.E., Gasparetto, C., Mukhopadhyay, S., Ondovik, M.S., Khan, M., Paley, C.S. and Lonial, S. (2013) PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 122, 2331-2337
67. Bradner, J.E., West, N., Grachan, M.L., Greenberg, E.F., Haggarty, S.J., Warnow, T. and Mazitschek, R. (2010) Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6, 238-243
68. Yardley, D.A., Ismail-Khan, R.R., Melichar, B., Lichinitser, M., Munster, P.N., Klein, P.M., Cruickshank, S., Miller, K.D., Lee, M.J. and Trepel, J.B. (2013) Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. 31, 2128-2135
69. Blum, K.A., Advani, A., Fernandez, L., Van Der Jagt, R., Brandwein, J., Kambhampati, S., Kassis, J., Davis, M., Bonfils, C., Dubay, M. et al. (2009) Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia. Br. J. Haematol. 147, 507-514
70. Dallavalle, S., Pisano, C. and Zunino, F. (2012) Development and therapeutic impact of HDAC6-selective inhibitors. Biochem. Pharmacol. 84, 756-765
71. Li, Y., Shin, D. and Kwon, S.H. (2013) Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J. 280, 775-793
72. Nielsen, T.K., Hildmann, C., Dickmanns, A., Schwienhorst, A. and Ficner, R. (2005) Crystal structure of a bacterial class 2 histone deacetylase homologue. J. Mol. Biol. 354, 107-120
73. Wang, D.F., Wiest, O., Helquist, P., Lan-Hargest, H.Y. and Wiech, N.L. (2004) On the function of the 14 A long internal cavity of histone deacetylase-like protein: implications for the design of histone deacetylase inhibitors. J. Med. Chem. 47, 3409-3417
74. Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M. and Schreiber, S.L. (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl. Acad. Sci. U.S.A. 100, 4389-4394
75. Haggarty, S.J., Koeller, K.M., Wong, J.C., Butcher, R.A. and Schreiber, S.L. (2003) Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays. Chem. Biol. 10, 383-396
76. Roy, A., Kucukural, A. and Zhang, Y. (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725-738
77. Arnott, J.A. and Planey, S.L. (2012) The influence of lipophilicity in drug discovery and design. Expert. Opin. Drug Discov. 7, 863-875
78. Oehme, I., Linke, J.P., Bock, B.C., Milde, T., Lodrini, M., Hartenstein, B., Wiegand, I., Eckert, C., Roth, W., Kool, M. et al. (2013) Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl. Acad. Sci. U.S.A. 110, E2592-E2601
79. Kalin, J.H., Butler, K.V., Akimova, T., Hancock, W.W. and Kozikowski, A.P. (2012) Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells. J. Med. Chem. 55, 639-651.
80. Santo, L., Hideshima, T., Kung, A.L., Tseng, J.C., Tamang, D., Yang, M., Jarpe, M., van Duzer, J.H., Mazitschek, R., Ogier, W.C. et al. (2012) Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119, 2579-2589
81. Dasmahapatra, G., Patel, H., Friedberg, J., Quayle, S.N., Jones, S.S. and Grant, S. (2014) In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells. Mol. Cancer Ther. 13, 2886-2897
82. Mishima, Y., Santo, L., Eda, H., Cirstea, D., Nemani, N., Yee, A.J., O'Donnell, E., Selig, M.K., Quayle, S.N., Arastu-Kapur, S. et al. (2015) Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br. J. Haematol. 169, 423-434
83. Amengual, J.E., Johannet, P., Lombardo, M., Zullo, K., Hoehn, D., Bhagat, G., Scotto, L., Jirau-Serrano, X., Radeski, D., Heinen, J. et al. (2015) Dual targeting of protein degradation pathways with the selective HDAC6 inhibitor ACY-1215 and bortezomib is synergistic in lymphoma. Clin. Cancer Res. 21, 4663-4675
84. Hideshima, T., Cottini, F., Ohguchi, H., Jakubikova, J., Gorgun, G., Mimura, N., Tai, Y.T., Munshi, N.C., Richardson, P.G. and Anderson, K.C. (2015) Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma. Blood Cancer J. 5, e312
85. Schafer, S., Saunders, L., Eliseeva, E., Velena, A., Jung, M., Schwienhorst, A., Strasser, A., Dickmanns, A., Ficner, R., Schlimme, S. et al. (2008) Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases (HDACs). Bioorg. Med. Chem. 16, 2011-2033
86. Schafer, S., Saunders, L., Schlimme, S., Valkov, V., Wagner, J.M., Kratz, F., Sippl, W., Verdin, E. and Jung, M. (2009) Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors. ChemMedChem 4, 283-290
87. Inks, E.S., Josey, B.J., Jesinkey, S.R. and Chou, C.J. (2012) A novel class of small molecule inhibitors of HDAC6. ACS Chem. Biol. 7, 331-339
88. Smil, D.V., Manku, S., Chantigny, Y.A., Leit, S., Wahhab, A., Yan, T.P., Fournel, M., Maroun, C., Li, Z., Lemieux, A.M. et al. (2009) Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 19, 688-692
89. Olsen, C.A. and Ghadiri, M,R. (2009) Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides. J. Med. Chem. 52, 7836-7846
90. Wahhab, A., Smil, D., Ajamian, A., Allan, M., Chantigny, Y., Therrien, E., Nguyen, N., Manku, S., Leit, S., Rahil, J. et al. (2009) Sulfamides as novel histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 19, 336-340
91. Itoh, Y., Suzuki, T., Kouketsu, A., Suzuki, N., Maeda, S., Yoshida, M., Nakagawa, H. and Miyata, N. (2007) Design, synthesis, structure-selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors. J. Med. Chem. 50, 5425-5438
92. Dehmel, F., Weinbrenner, S., Julius, H., Ciossek, T., Maier, T., Stengel, T., Fettis, K., Burkhardt, C., Wieland, H. and Beckers, T. (2008) Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacological profiles. J. Med. Chem. 51, 3985-4001
93. Kozikowski, A.P., Chen, Y., Gaysin, A., Chen, B., D'Annibale, M.A., Suto, C.M. and Langley, B.C. (2007) Functional differences in epigenetic modulators-superiority of mercaptoacetamide-based histone deacetylase inhibitors relative to hydroxamates in cortical neuron neuroprotection studies. J. Med. Chem. 50, 3054-3061
94. Olzmann, J.A., Li, L. and Chin, L.S. (2008) Aggresome formation and neurodegenerative diseases: therapeutic implications. Curr. Med. Chem. 15, 47-60
95. Pandey, U.B., Nie, Z., Batlevi, Y., McCray, B.A., Ritson, G.P., Nedelsky, N.B., Schwartz, S.L., DiProspero, N.A., Knight, M.A., Schuldiner, O. et al. (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859-863
96. Du, G., Liu, X., Chen, X., Song, M., Yan, Y., Jiao, R. and Wang, C.C. (2010) Drosophila histone deacetylase 6 protects dopaminergic neurons against (alpha)-synuclein toxicity by promoting inclusion formation. Mol. Biol. Cell 21, 2128-2137
97. Narendra, D., Tanaka, A., Suen, D.F. and Youle, R.J. (2009) Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy 5, 706-708
98. Lee, J.Y., Nagano, Y., Taylor, J.P., Lim, K.L. and Yao, T.P. (2010) Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J. Cell Biol. 189, 671-679
99. Olzmann, J.A., Li, L., Chudaev, M.V., Chen, J., Perez, F.A., Palmiter, R.D. and Chin, L.S. (2007) Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J. Cell Biol. 78, 1025-1038
100. Lev, N., Roncevic, D., Ickowicz, D., Melamed, E. and Offen, D. (2006) Role of DJ-1 in Parkinson's disease. J. Mol. Neurosci. 29, 215-225
101. Zhang, L., Sheng, S. and Qin, C. (2013) The role of HDAC6 in Alzheimer's disease. J. Alzheimers Dis. 33, 283-295
102. Mandelkow, E.M. and Mandelkow, E. (1998) Tau in Alzheimer's disease. Trends Cell Biol. 8, 425-527
103. Williams, D.R. (2006) Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern. Med. J. 36, 652-660
104. Ding, H., Dolan, P.J. and Johnson, G.V. (2008) Histone deacetylase 6 interacts with the microtubule-associated protein tau. J. Neurochem. 106, 2119-2130
105. Karagoz, G.E., Duarte, A.M., Akoury, E., Ippel, H., Biernat, J., Moran Luengo, T., Radli, M., Didenko, T., Nordhues, B.A., Veprintsev, D.B. et al. (2014) Hsp90-Tau complex reveals molecular basis for specificity in chaperone action. Cell 156, 963-974
106. Cook, C., Gendron, T.F., Scheffel, K., Carlomagno, Y., Dunmore, J., DeTure, M. and Petrucelli, L. (2012) Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation. Hum. Mol. Genet. 21, 2936-2945
107. Xiong, Y., Zhao, K., Wu, J., Xu, Z., Jin, S. and Zhang, Y.Q. (2013) HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila. Proc. Natl. Acad. Sci. U.S.A. 110, 4604-4609
108. Perez, M., Santa-Maria, I., Gomez de Barreda, E., Zhu, X., Cuadros, R., Cabrero, J.R., Sanchez-Madrid, F., Dawson, H.N., Vitek, M.P., Perry, G. et al. (2009) Tau-an inhibitor of deacetylase HDAC6 function. J. Neurochem. 109, 1756-1766
109. Zhang, L., Liu, C., Wu, J., Tao, J.J., Sui, X.L., Yao, Z.G., Xu, Y.F., Huang, L., Zhu, H., Sheng, S.L. and Qin, C. (2014) Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice. J. Alzheimers Dis. 41, 1193-1205
110. Selenica, M.L., Benner, L., Housley, S.B., Manchec, B., Lee, D.C., Nash, K.R., Kalin, J., Bergman, J.A., Kozikowski, A., Gordon, M.N. and Morgan, D. (2014) Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition. Alzheimers Res. Ther. 6, 12
111. Hatters, D.M. (2008) Protein misfolding inside cells: the case of huntingtin and Huntington's disease. IUBMB Life 60, 724-728
112. Trushina, E., Heldebrant, M.P., Perez-Terzic, C.M., Bortolon, R., Kovtun, I.V., Badger, J.D., 2nd, Terzic, A., Estevez, A., Windebank, A.J., Dyer, R.B. et al. (2003) Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease. Proc. Natl. Acad. Sci. U.S.A. 100, 12171-12176
113. Dompierre, J.P., Godin, J.D., Charrin, B.C., Cordelieres, F.P., King, S.J., Humbert, S. and Saudou, F. (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571-3583
114. Guedes-Dias, P., de Proenca, J., Soares, T.R., Leitao-Rocha, A., Pinho, B.R., Duchen, M.R. and Oliveira, J.M. (2015) HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons. Biochim. Biophys. Acta 1852, 2484-2493
115. Evgrafov, O.V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C.L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V. et al. (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat. Genet. 36, 602-606
116. d'Ydewalle, C., Krishnan, J., Chiheb, D.M., Van Damme, P., Irobi, J., Kozikowski, A.P., Vanden Berghe, P., Timmerman, V., Robberecht, W. and Van Den Bosch, L. (2011) HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat. Med. 17, 968-974
117. Rodriguez-Gonzalez, A., Lin, T., Ikeda, A.K., Simms-Waldrip, T., Fu, C. and Sakamoto, K.M. (2008) Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation. Cancer Res. 68, 2557-2560
118. Hideshima, T., Bradner, J.E., Wong, J., Chauhan, D., Richardson, P., Schreiber, S.L. and Anderson, K.C. (2005) Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc. Natl. Acad. Sci. U.S.A. 102, 8567-8572
119. Zhang, Z., Yamashita, H., Toyama, T., Sugiura, H., Omoto, Y., Ando, Y., Mita, K., Hamaguchi, M., Hayashi, S. and Iwase, H. (2004) HDAC6 expression is correlated with better survival in breast cancer. Clin. Cancer Res. 10, 6962-6968
120. Saji, S., Kawakami, M., Hayashi, S., Yoshida, N., Hirose, M., Horiguchi, S., Itoh, A., Funata, N., Schreiber, S.L., Yoshida, M. and Toi, M. (2005) Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene 24, 4531-4539
121. Bazzaro, M., Lin, Z., Santillan, A., Lee, M.K., Wang, M.C., Chan, K.C., Bristow, R.E., Mazitschek, R., Bradner, J. and Roden, R.B. (2008) Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Clin. Cancer Res. 14, 7340-7347
122. Sakuma, T., Uzawa, K., Onda, T., Shiiba, M., Yokoe, H., Shibahara, T. and Tanzawa, H. (2006) Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Int. J. Oncol. 29, 117-124
123. Bradbury, C.A., Khanim, F.L., Hayden, R., Bunce, C.M., White, D.A., Drayson, M.T., Craddock, C. and Turner, B.M. (2005) Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 19, 1751-1759
124. Inoue, A., Yoshida, N., Omoto, Y., Oguchi, S., Yamori, T., Kiyama, R. and Hayashi, S. (2002) Development of cDNA microarray for expression profiling of estrogen-responsive genes. J. Mol. Endocrinol. 29, 175-192
125. Dunnwald, L.K., Rossing, M.A. and Li, C.I. (2007) Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 9, R6
126. Aldana-Masangkay, G.I. and Sakamoto, K.M. (2011) The role of HDAC6 in cancer. J. Biomed. Biotechnol. 2011, 875824
127. Lee, Y.S., Lim, K.H., Guo, X., Kawaguchi, Y., Gao, Y., Barrientos, T., Ordentlich, P., Wang, X.F., Counter, C.M. and Yao, T.P. (2008) The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis. Cancer Res. 68, 7561-7569
128. Geiger, T.R. and Peeper, D.S. (2007) Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Res. 67, 6221-6229
129. Murphy, P.J., Morishima, Y., Kovacs, J.J., Yao, T.P. and Pratt, W.B. (2005) Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone. J. Biol. Chem. 280, 33792-33799
130. Ai, J., Wang, Y., Dar, J.A., Liu, J., Liu, L., Nelson, J.B. and Wang, Z. (2009) HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer. Mol. Endocrinol. 23, 1963-1972
131. Li, Y., Zhang, X., Polakiewicz, R.D., Yao, T.P. and Comb, M.J. (2008) HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J. Biol. Chem. 283, 12686-12690
132. Mak, A.B., Nixon, A.M., Kittanakom, S., Stewart, J.M., Chen, G.I., Curak, J., Gingras, A.C., Mazitschek, R., Neel, B.G., Stagljar, I. and Moffat, J. (2012) Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation. Cell Rep 2, 951-963
133. Weaver, A.M. (2008) Cortactin in tumor invasiveness. Cancer Lett. 265, 157-166
134. Rey, M., Irondelle, M., Waharte, F., Lizarraga, F. and Chavrier, P. (2011) HDAC6 is required for invadopodia activity and invasion by breast tumor cells. Eur. J. Cell Biol. 90, 128-135
135. Castro-Castro, A., Janke, C., Montagnac, G., Paul-Gilloteaux, P. and Chavrier, P. (2012) ATAT1/MEC-17 acetyltransferase and HDAC6 deacetylase control a balance of acetylation of alpha-tubulin and cortactin and regulate MT1-MMP trafficking and breast tumor cell invasion. Eur. J. Cell Biol. 91, 950-960
136. Arsenault, D., Brochu-Gaudreau, K., Charbonneau, M. and Dubois, C.M. (2013) HDAC6 deacetylase activity is required for hypoxia-induced invadopodia formation and cell invasion. PloS One 8, e55529
137. Kayali, F., Montie, H.L., Rafols, J.A. and DeGracia, D.J. (2005) Prolonged translation arrest in reperfused hippocampal cornu Ammonis 1 is mediated by stress granules. Neuroscience 134, 1223-1245
138. Buchan, J.R. and Parker, R. (2009) Eukaryotic stress granules: the ins and outs of translation. Mol. Cell 36, 932-941
139. Kwon, S., Zhang, Y. and Matthias, P. (2007) The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. 21, 3381-3394
140. Somasekharan, S.P., El-Naggar, A., Leprivier, G., Cheng, H., Hajee, S., Grunewald, T.G., Zhang, F., Ng, T., Delattre, O., Evdokimova, V. et al. (2015) YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1. J. Cell Biol. 208, 913-929
141. Lemon, D.D., Horn, T.R., Cavasin, M.A., Jeong, M.Y., Haubold, K.W., Long, C.S., Irwin, D.C., McCune, S.A., Chung, E., Leinwand, L.A. and McKinsey, T.A. (2011) Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension. J. Mol. Cell Cardiol. 51, 41-50
142. Kee, H.J., Bae, E.H., Park, S., Lee, K.E., Suh, S.H., Kim, S.W. and Jeong, M.H. (2013) HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity. Kidney Blood Press. Res. 37, 229-239
143. Demos-Davies, K.M., Ferguson, B.S., Cavasin, M.A., Mahaffey, J.H., Williams, S.M., Spiltoir, J.I., Schuetze, K.B., Horn, T.R., Chen, B., Ferrara, C. et al. (2014) HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling. Am. J. Physiol. Heart Circ. Physiol. 307, H252-H258
144. Aune, S.E., Herr, D.J., Mani, S.K. and Menick, D.R. (2014) Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion. J. Mol. Cell. Cardiol. 72, 138-145
145. Zhang, D., Wu, C.T., Qi, X., Meijering, R.A., Hoogstra-Berends, F., Tadevosyan, A., Cubukcuoglu Deniz, G., Durdu, S., Akar, A.R., Sibon, O.C. et al. (2014) Activation of histone deacetylase-6 induces contractile dysfunction through derailment of alpha-tubulin proteostasis in experimental and human atrial fibrillation. Circulation 129, 346-358
146. McLendon, P.M., Ferguson, B.S., Osinska, H., Bhuiyan, M.S., James, J., McKinsey, T.A. and Robbins, J. (2014) Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy. Proc. Natl. Acad. Sci. U.S.A. 111, E5178-E5186
147. De Meyer, G.R., De Keulenaer, G.W. and Martinet, W. (2010) Role of autophagy in heart failure associated with aging. Heart Fail. Rev. 15, 423-430
148. Ferguson, B.S. and McKinsey, T.A. (2015) Non-sirtuin histone deacetylases in the control of cardiac aging. J. Mol. Cell. Cardiol. 83, 14-20
149. de Zoeten, E.F., Wang, L., Butler, K., Beier, U.H., Akimova, T., Sai, H., Bradner, J.E., Mazitschek, R., Kozikowski, A.P., Matthias, P. and Hancock, W.W. (2011) Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol. Cell. Biol. 31, 2066-2078
150. Vishwakarma, S., Iyer, L.R., Muley, M., Singh, P.K., Shastry, A., Saxena, A., Kulathingal, J., Vijaykanth, G., Raghul, J., Rajesh, N. et al. (2013) Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int. Immunopharmacol. 16, 72-78
151. Cheng, X., Liu, Z., Liu, B., Zhao, T., Li, Y. and Alam, H.B. (2015) Selective histone deacetylase 6 inhibition prolongs survival in a lethal two-hit model. J. Surg. Res. 197, 39-44
152. Wang, B., Rao, Y.H., Inoue, M., Hao, R., Lai, C.H., Chen, D., McDonald, S.L., Choi, M.C., Wang, Q., Shinohara, M.L. and Yao, T.P. (2014) Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat. Commun. 5, 3479
153. Cheng, F., Lienlaf, M., Wang, H.W., Perez-Villarroel, P., Lee, C., Woan, K., Rock-Klotz, J., Sahakian, E., Woods, D., Pinilla-Ibarz, J. et al. (2014) A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J. Immunol. 193, 2850-2862
154. Cheng, F., Lienlaf, M., Perez-Villarroel, P., Wang, H.W., Lee, C., Woan, K., Woods, D., Knox, T., Bergman, J., Pinilla-Ibarz, J. et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol. Immunol. 60, 44-53
155. Di Liddo, R., Valente, S., Taurone, S., Zwergel, C., Marrocco, B., Turchetta, R., Conconi, M.T., Scarpa, C., Bertalot, T., Schrenk, S. et al. (2016) Histone deacetylase inhibitors restore IL-10 expression in lipopolysaccharide-induced cell inflammation and reduce IL-1beta and IL-6 production in breast silicone implant in C57BL/6J wild-type murine model. Autoimmunity
156. Espallergues, J., Teegarden, S.L., Veerakumar, A., Boulden, J., Challis, C., Jochems, J., Chan, M., Petersen, T., Deneris, E., Matthias, P. et al. (2012) HDAC6 regulates glucocorticoid receptor signaling in specific activity pathways with critical impact on stress resilience. J. Neurosci. 32, 4400-4416
157. Fukada, M., Hanai, A., Nakayama, A., Suzuki, T., Miyata, N., Rodriguiz, R.M., Wetsel, W.C., Yao, T.P. and Kawaguchi, Y. (2012) Loss of deacetylation activity of Hdac6 affects emotional behavior in mice. PloS One 7, e30924
158. Lee, J.B., Wei, J., Liu, W., Cheng, J., Feng, J. and Yan, Z. (2012) Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex. J. Physiol. 590, 1535-1546
159. Jochems, J., Boulden, J., Lee, B.G., Blendy, J.A., Jarpe, M., Mazitschek, R., Van Duzer, J.H., Jones, S. and Berton, O. (2014) Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology 39, 389-400
160. Brocco, M., Dekeyne, A., Veiga, S., Girardon, S. and Millan, M.J. (2002) Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents. Pharmacol. Biochem. Behav. 71, 667-680
161. Sadoul, K., Wang, J., Diagouraga, B., Vitte, A.L., Buchou, T., Rossini, T., Polack, B., Xi, X., Matthias, P. and Khochbin, S. (2012) HDAC6 controls the kinetics of platelet activation. Blood 120, 4215-4218
162. Behnke, O. (1970) Microtubules in disk-shaped blood cells. Int. Rev. Exp. Pathol. 9, 1-92
163. Aslan, J.E., Phillips, K.G., Healy, L.D., Itakura, A., Pang, J. and McCarty, O.J. (2013) Histone deacetylase 6-mediated deacetylation of alpha-tubulin coordinates cytoskeletal and signaling events during platelet activation. Am. J. Physiol. Cell Physiol. 305, C1230-C1239
164. Shan, B., Yao, T.P., Nguyen, H.T., Zhuo, Y., Levy, D.R., Klingsberg, R.C., Tao, H., Palmer, M.L., Holder, K.N. and Lasky, J.A. (2008) Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition. J. Biol. Chem. 283, 21065-21073
165. Gu, S., Liu, Y., Zhu, B., Ding, K., Yao, T.P., Chen, F., Zhan, L., Xu, P., Ehrlich, M., Liang, T. et al. (2016) Loss of alpha-tubulin acetylation is associated with TGF-beta-induced epithelial-mesenchymal transition. J. Biol. Chem. 291, 5396-5405
166. Choi, S.Y., Ryu, Y., Kee, H.J., Cho, S.N., Kim, G.R., Cho, J.Y., Kim, H.S., Kim, I.K. and Jeong, M.H. (2015) Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes. Vascul. Pharmacol. 72, 130-140
167. Gradilone, S.A., Habringer, S., Masyuk, T.V., Howard, B.N., Masyuk, A.I. and Larusso, N.F. (2014) HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. Am. J. Pathol. 184, 600-608
168. Mergen, M., Engel, C., Muller, B., Follo, M., Schafer, T., Jung, M. and Walz, G. (2013) The nephronophthisis gene product NPHP2/Inversin interacts with Aurora A and interferes with HDAC6-mediated cilia disassembly. Nephrol. Dial. Transplant. 28, 2744-2753
169. Singla, V. and Reiter, J.F. (2006) The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313, 629-633
170. Kobayashi, T. and Dynlacht, B.D. (2011) Regulating the transition from centriole to basal body. J. Cell Biol. 193, 435-444
171. Pan, J. and Snell, W. (2007) The primary cilium: keeper of the key to cell division. Cell 129, 1255-1257
172. Pugacheva, E.N., Jablonski, S.A., Hartman, T.R., Henske, E.P. and Golemis, E.A. (2007) HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351-1363
173. Wilson, P.D. (2004) Polycystic kidney disease. N. Engl. J. Med. 350, 151-164
174. Gao, Y.S., Hubbert, C.C. and Yao, T.P. (2010) The microtubule-associated histone deacetylase 6 (HDAC6) regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation. J. Biol. Chem. 285, 11219-11226
175. Richards, W.G., Sweeney, W.E., Yoder, B.K., Wilkinson, J.E., Woychik, R.P. and Avner, E.D. (1998) Epidermal growth factor receptor activity mediates renal cyst formation in polycystic kidney disease. J. Clin. Invest. 101, 935-939
176. Liu, W., Fan, L.X., Zhou, X., Sweeney, Jr, W.E., Avner, E.D. and Li, X. (2012) HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PloS One 7, e49418
177. Cebotaru, V., Cebotaru, L., Kim, H., Chiaravalli, M., Boletta, A., Qian, F. and Guggino, W.B. (2014) Polycystin-1 negatively regulates Polycystin-2 expression via the aggresome/autophagosome pathway. J. Biol. Chem. 289, 6404-6414