Mice Lacking Histone Deacetylase 6 Have Hyperacetylated Tubulin but Are Viable and Develop Normally
Open accessAbstract
Posttranslational modifications play important roles in regulating protein structure and function. Histone deacetylase 6 (HDAC6) is a mostly cytoplasmic class II HDAC, which has a unique structure with two catalytic domains and a domain binding ubiquitin with high affinity. This enzyme was recently identified as a multisubstrate protein deacetylase that can act on acetylated histone tails, alpha-tubulin and Hsp90. To investigate the in vivo functions of HDAC6 and the relevance of tubulin acetylation/deacetylation, we targeted the HDAC6 gene by homologous recombination in embryonic stem cells and generated knockout mice. HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues. The highest level of expression of HDAC6 is seen in the testis, yet development and function of this organ are normal in the absence of HDAC6. Likewise, lymphoid development is normal, but the immune response is moderately affected. Furthermore, the lack of HDAC6 results in a small increase in cancellous bone mineral density, indicating that this deacetylase plays a minor role in bone biology. HDAC6-deficient mouse embryonic fibroblasts show apparently normal microtubule organization and stability and also show increased Hsp90 acetylation correlating with impaired Hsp90 function. Collectively, these data demonstrate that mice survive well without HDAC6 and that tubulin hyperacetylation is not detrimental to normal mammalian development.
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HDAC6 is a tubulin deacetylase and the main tubulin deacetylase.
“HDAC6, a tubulin deacetylase [24].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [32]
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HDAC6 is a microtubule-associated deacetylase
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Sharabi, A., Tsokos, M., Ding, Y., Malek, T. R., Klatzmann, D., & Tsokos, G. C. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.148 · Cited by 297 · see citing works
Acetylation site specificities of lysine deacetylase inhibitors in human cells
Schölz, C., Weinert, B. T., Wagner, S., Beli, P., Miyake, Y., Qi, J., Jensen, L. J., Streicher, W. W., McCarthy, A. R., Westwood, N. J., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3130 · Cited by 271 · see citing works
Self-citationHistone Deacetylase 6 and Heat Shock Protein 90 Control the Functions of Foxp3 + T-Regulatory Cells
de Zoeten, E. F., Wang, L., Butler, K. V., Beier, U. H., Akimova, T., Sai, H., Bradner, J. E., Mazitschek, R., Kozikowski, A. P., Matthias, P., et al. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05155-11 · Cited by 257 · see citing works
“HDAC6-selective inhibitors (HDAC6i) (8, 12, 22, 28, 46, 48, 50) and HDAC6 / mice (20, 62) have been developed.”
Self-citationInfluenza A virus uses the aggresome processing machinery for host cell entry
Banerjee, I., Miyake, Y., Nobs, S. P., Schneider, C., Horváth, P., Köpf, M., Matthias, P., Helenius, A., & Yamauchi, Y. (2014) · Science · doi:10.1126/science.1257037 · Cited by 276 · see citing works
Self-citationThe Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis
Lee, Y.-S., Lim, K.-H., Guo, X., Kawaguchi, Y., Gao, Y., Barrientos, T., Ordentlich, P., Wang, X.-F., Counter, C. M., & Yao, T.-P. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0188 · Cited by 260 · see citing works
“Importantly, as HDAC6 is not an essential gene and HDAC6-null mice are grossly normal (14, 56), our study further suggests that HDAC6 might be an ideal target for the design of chemotherapeutic agents for its low toxicity.”
BackgroundCilium assembly and disassembly
Sánchez, I., & Dynlacht, B. D. (2016) · Nature Cell Biology · doi:10.1038/ncb3370 · Cited by 279 · see citing works
Engin, F., & Hotamışlıgil, G. S. (2010) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2010.01282.x · Cited by 245 · see citing works
“HDAC6 has also been showed to act as a tubulin deacetylase and involved in the transport of misfolded proteins to the proteasome pathway for degradation, possibly, through its effects on the microtubules [38].”
BackgroundTubulin acetylation: responsible enzymes, biological functions and human diseases
Li, L., & Yang, X. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2000-5 · Cited by 257 · see citing works
“By contrast, deletion of the mouse Hdac6 gene leads to global a-tubulin hyperacetylation [67], indicating that HDAC6 is a major tubulin deacetylase in vivo.”
InfluentialRegulation of microtubule dynamics by inhibition of the tubulin deacetylase HDAC6
Zilberman, Y., Ballestrem, C., Carramusa, L., Mazitschek, R., Khochbin, S., & Bershadsky, A. D. (2009) · Journal of Cell Science · doi:10.1242/jcs.046813 · Cited by 242 · see citing works
“At the same time, several other studies claimed that increased microtubule acetylation had no effect on the dynamic behavior of microtubules (Haggarty et al., 2003; Palazzo et al., 2003; Zhang et al., 2008).”
BackgroundResultInfluentialSelf-citationThe perennial organelle: assembly and disassembly of the primary cilium
Seeley, E. S., & Nachury, M. V. (2010) · Journal of Cell Science · doi:10.1242/jcs.061093 · Cited by 224 · see citing works
“Furthermore, knocking out the Hdac6 gene in mice produces only subtle immunological phenotypes rather than the gross abnormalities and embryonic lethality (Zhang et al., 2008) that would be expected if the lack of this protein caused hyperstable microtubules or persistent cilia.”
BackgroundMaxwell, M. M., Tomkinson, E. M., Nobles, J., Wizeman, J. W., Amore, A. M., Quinti, L., Chopra, V., Hersch, S. M., & Kazantsev, A. G. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr326 · Cited by 209 · see citing works
Isoform-specific histone deacetylase inhibitors: The next step?
Balasubramanian, S., Verner, E. J., & Buggy, J. J. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.02.013 · Cited by 224 · see citing works
“Finally, HDAC6 knockouts are viable, and are the only HDAC mutant mice with no obvious phenotype except for increased tubulin acetylation [37].”
BackgroundThe ins and outs of tubulin acetylation: More than just a post-translational modification?
Perdiz, D., Mackeh, R., Poüs, C., & Baillet, A. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.10.014 · Cited by 206 · see citing works
HDAC6 Inhibition Restores Ciliary Expression and Decreases Tumor Growth
Gradilone, S. A., Radtke, B. N., Bogert, P. S. T., Huang, B. Q., Gajdos, G. B., & LaRusso, N. F. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2938 · Cited by 225 · see citing works
“The fact that mice lacking HDAC6 are viable and develop normally (49) suggests that HDAC6-specific targeting may have minimal adverse effects.”
αTAT1 is the major α-tubulin acetyltransferase in mice
Kalebic, N., Sorrentino, S., Perlas, E., Bolasco, G., Martinez, C., & Heppenstall, P. A. (2013) · Nature Communications · doi:10.1038/ncomms2962 · Cited by 241 · see citing works
Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin
Kaluza, D., Krøll, J., Gesierich, S., Yao, T., Boon, R. A., Hergenreider, E., Tjwa, M., Rössig, L., Seto, E., Augustin, H. G., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.298 · Cited by 196 · see citing works
Targeting histone deacetylases for cancer therapy: Trends and challenges
Liang, T., Wang, F., Elhassan, R. M., Cheng, Y., Tang, X., Chen, W., Fang, H., & Hou, X. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.02.007 · Cited by 222 · see citing works
Beier, U. H., Wang, L., Han, R., Akimova, T., Liu, Y., & Hancock, W. W. (2012) · Science Signaling · doi:10.1126/scisignal.2002873 · Cited by 205 · see citing works
“Mice C57BL/6 and B6/Rag1 (Jackson Laboratory), B6/129 (Taconic), HDAC6 (30), HDAC9 (31), fl-Sirt1/CD4cre (10), fl-Sirt1/Foxp3cre (10), and Hsp70 (32) mice, all on an H-2 background, were housed under specific pathogen–free conditions and were studied under a protocol approved by the Institutional Animal Care and Use C…”
MethodRegulation of Epidermal Growth Factor Receptor Trafficking by Lysine Deacetylase HDAC6
Lissanu, Y., Wild, P. S., Chandrashaker, A., Ćurak, J., Schmidt, M. H. H., Kalaidzidis, Y. L., Milutinovic, N., Kratchmarova, I., Bürkle, L., Fetchko, M. J., et al. (2009) · Science Signaling · doi:10.1126/scisignal.2000576 · Cited by 176 · see citing works
“In this process, HDAC6 is likely to play a fine-tuning role, which may explain the lack of gross developmental defects and obvious phenotypic changes in EGFR-dependent processes in HDAC6-knockout mice (34).”
BackgroundRao, R., Fiskus, W. C., Yang, Y., Lee, P., Joshi, R., Fernandez, P., Mandawat, A., Atadja, P. W., Bradner, J. E., & Bhalla, K. N. (2008) · Blood · doi:10.1182/blood-2008-03-143644 · Cited by 189 · see citing works
Regulation of CD133 by HDAC6 Promotes β-Catenin Signaling to Suppress Cancer Cell Differentiation
Mak, A. B., Nixon, A. M. L., Kittanakom, S., Stewart, J. M., Chen, G. I., Ćurak, J., Gingras, A., Mazitschek, R., Neel, B. G., Štagljar, I., et al. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.09.016 · Cited by 183 · see citing works
“Importantly, HDAC6 appears to be dispensable in the normal mouse physiology and development (Zhang et al., 2008), as HDAC6 knockout mice are viable and healthy and do not show any malignant predispositions.”
BackgroundPosttranslational Modifications of Tubulin and Cilia
Wloga, D., Joachimiak, E., Louka, P., & Gaertig, J. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028159 · Cited by 183 · see citing works
“The HDAC6 knockout mouse lacks ciliary phenotypes (Zhang et al. 2008), but the loss of HDAC6 could be covered by SIRT2.”
BackgroundHalili, M. A., Andrews, M. R., Labzin, L. I., Schroder, K., Matthias, G., Cao, C., Lovelace, E., Reid, R. C., Le, G. T., Hume, D. A., et al. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0509363 · Cited by 186 · see citing works
“To assess the selectivity of MS-275, compound 17a, and compound 7 in macrophages, we first examined the hyperacetylation of HDAC substrates, HDAC1 and HDAC6 deacetylate histone H3, [35] and -tubulin [39], respectively.”
BackgroundSelf-citationCilium structure, assembly, and disassembly regulated by the cytoskeleton
Mirvis, M., Stearns, T., & Nelson, W. J. (2018) · Biochemical Journal · doi:10.1042/bcj20170453 · Cited by 191 · see citing works
Yee, A. J., Bensinger, W., Supko, J. G., Voorhees, P. M., Berdeja, J. G., Richardson, P. G. G., Libby, E. N., Wallace, E. E., Birrer, N., Burke, J. N., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30375-8 · Cited by 205 · see citing works
Bergman, J. A., Woan, K. V., Perez-Villarroel, P., Villagra, A., Sotomayor, E. M., & Kozikowski, A. P. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301098e · Cited by 200 · see citing works
From signaling pathways to microtubule dynamics: the key players
Etienne‐Manneville, S. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.11.008 · Cited by 163 · see citing works
“In agreement, the tubulin deacetylase HDAC6-deficient mice show hyperacetylated tubulin in most tissues but develop normally [37].”
BackgroundMechanisms of Oocyte Maturation and Related Epigenetic Regulation
He, M., Zhang, T., Yang, Y., & Wang, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.654028 · Cited by 173 · see citing works
“However, HDAC6 KO mice are viable and fertile and presented no major observable phenotype (Zhang et al., 2008).”
BackgroundComprehensive lysine acetylomes emerging from bacteria to humans
Kim, G.-W., & Yang, X. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.10.001 · Cited by 165 · see citing works
Jochems, J., Boulden, J., Lee, B. G., Blendy, J. A., Jarpe, M. B., Mazitschek, R., van Duzer, J. H., Jones, S. S., & Berton, O. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.207 · Cited by 168 · see citing works
“In contrast to class I isoforms, the loss of function of HDAC6 does not produce toxicity, apoptosis, or major neurodevelopmental defects in rodents (Govindarajan et al, 2012; Haberland et al, 2009; Zhang et al, 2008).”
Post-translational modifications of Hsp90 and translating the chaperone code
Backe, S. J., Sager, R., Woodford, M. R., Makedon, A. M., & Mollapour, M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011833 · Cited by 208 · see citing works
Knox, T., Sahakian, E., Banik, D., Hadley, M., Palmer, E., Noonepalle, S., Kim, J., Powers, J., Gracia-Hernandez, M., Oliveira, V., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-42237-3 · Cited by 170 · see citing works
Tau – an inhibitor of deacetylase HDAC6 function
Perez, M., Santa‐Maria, I., De Barreda, E. G., Zhu, X., Cuadros, R., Cabrero, J. R., Sanchez‐Madrid, F., Dawson, H. N., Vitek, M. P., Perry, G., et al. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06102.x · Cited by 182 · see citing works
“However, while HDAC6 knockout mice have hyperacetylated tubulin, they are viable and develop normally, without neurological abnormalities (Zhang et al. 2008).”
BackgroundChromatin Remodeling in Cardiovascular Development and Physiology
Han, P., Hang, C. T., Yang, J., & Chang, C. (2011) · Circulation Research · doi:10.1161/circresaha.110.224287 · Cited by 165 · see citing works
Feig, J. E., Shang, Y., Rotllán, N., Vengrenyuk, Y., Wu, C., Shamir, R., Pineda‐Torra, I., Fernandez-Hernando, C. F., Fisher, E. A. A., & Garabedian, M. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028534 · Cited by 151 · see citing works
“Although HDAC7 mice are embryonic lethal [27], HADC6 deficient mice are viable and fertile [28], and it will be interesting to see in future studies if regression of atherosclerosis is”
Brunden, K. R., Yao, Y., Potuzak, J. S., Ferrer, N. I., Ballatore, C., James, M. J., Hogan, A. L., Trojanowski, J. Q., Smith, A. B., & Lee, V. M. ‐. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.12.002 · Cited by 159 · see citing works
“In fact, a recent study demonstrated that immunoprecipitation of acetyl-tubulin from mouse brain homogenates resulted in the capture of essentially all of the α-tubulin, indicating that there was virtually no α-tubulin that was deacetylated [49].”
BackgroundResultInfluentialLi, Z., & Zhu, W. (2014) · International Journal of Biological Sciences · doi:10.7150/ijbs.9067 · Cited by 160 · see citing works
“Overexpression of HDAC6 promotes cell mobility, but deletion of HDAC6 has no effect on normal development and disease progression in mice model [162, 163].”
BackgroundThe Tale of Protein Lysine Acetylation in the Cytoplasm
Sadoul, K., Wang, J., Diagouraga, B., & Khochbin, S. (2010) · BioMed Research International · doi:10.1155/2011/970382 · Cited by 140 · see citing works
“The reason for this may come from the fact that the expression of nonacetylatable α-tubulin does not result in any obvious phenotype [104–106], nor does hyperacetylation following KO of HDAC6 [107].”
BackgroundSelf-citationCell cycle progression by the repression of primary cilia formation in proliferating cells
Goto, H., Inoko, A., & Inagaki, M. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1302-8 · Cited by 153 · see citing works
“HDAC6 knockout mice showed hyperacetylated tubulin in most tissues, but did not reveal apparent phenotypes that would be expected to result from aberrant ciliary formation [71].”
Tubulin Post-Translational Modifications and Microtubule Dynamics
Włoga, D., Joachimiak, E., & Fabczak, H. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102207 · Cited by 163 · see citing works
“elegans known as Mec-17) is the main, if not the only, acetyltransferase for K40 [11,12], and the reverse reaction is catalyzed by the deacetylases: Sirt2 (Sirtuin type 2) [13] or histone deacetylase HDAC6 [14], which is the major tubulin deacetylases in vivo [15].”
BackgroundHistone Deacetylases in Bone Development and Skeletal Disorders
Bradley, E. W., Shull, L. C., van Wijnen, A. J., McGee‐Lawrence, M. E., & Westendorf, J. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00004.2015 · Cited by 163 · see citing works
Espallergues, J., Teegarden, S. L., Veerakumar, A., Boulden, J., Challis, C., Jochems, J., Chan, M., Petersen, T. L., Deneris, E. S., Matthias, P., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5634-11.2012 · Cited by 147 · see citing works
“To generate a mouse line with a selective inactivation of the HDAC6 gene in serotonin neurons, male BAC transgenic Pet1-Cre mice (Scott et al., 2005) were crossed to flHDAC6 females in which a portion of HDAC6 gene (exons 8 –10) is floxed (Zhang et al., 2008).”
BackgroundMethodResultInfluentialSelf-citationBobrowska, A., Donmez, G., Weiss, A., Guarente, L., & Bates, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034805 · Cited by 140 · see citing works
“Consistent with this, previous studies could not detect changes in the levels of acetylated tubulin in mouse embryonic fibroblasts derived from Sirt2KO mice [41].”
ResultMIM and Cortactin Antagonism Regulates Ciliogenesis and Hedgehog Signaling
Bershteyn, M., Atwood, S. X., Woo, W., Covington, M. L., & Oro, A. E. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.07.009 · Cited by 137 · see citing works
“However, another study found that HDAC6 mutant mice were viable and had normal cilia (Zhang et al., 2008), prompting us to ask whether inhibition of HDAC6 could prevent cilia disassembly in MIM KD cells.”
BackgroundCheng, 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) · Molecular Immunology · doi:10.1016/j.molimm.2014.02.019 · Cited by 140 · see citing works
“Second, similar results were obtained in peritoneal elicited macrophages (PEM) and dendritic cells (DC) isolated from HDAC6 knock out (HDAC6 KO) mice(Zhang et al., 2008).”
InfluentialLee, J., Kapur, M., Li, M., Choi, M., Choi, S., Kim, H.-J., Kim, I., Lee, E. J., Taylor, J. P., & Yao, T. (2014) · Journal of Cell Science · doi:10.1242/jcs.157321 · Cited by 132 · see citing works
Histone Deacetylase Inhibitors in Cell Pluripotency, Differentiation, and Reprogramming
Kretsovali, A., Hadjimichael, C., & Charmpilas, N. (2012) · Stem Cells International · doi:10.1155/2012/184154 · Cited by 126 · see citing works
“Members of the HDAC class IIb group (HDAC 6, 10) regulate cytoskeletal dynamics by controlling the acetylation of cytoskeletal proteins such as tubulin [32].”
BackgroundHistone deacetylases and epigenetic therapies of hematological malignancies
Mercurio, C., Minucci, S., & Pelicci, P. G. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.02.010 · Cited by 125 · see citing works
Ai, J., Wang, Y., Dar, J. A., Liu, J., Liu, L., Nelson, J. B., & Wang, Z. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0188 · Cited by 126 · see citing works
Loss of Deacetylation Activity of Hdac6 Affects Emotional Behavior in Mice
Fukada, M., Hanai, A., Nakayama, A., Suzuki, T., Miyata, N., Rodriguiz, R. M., Wetsel, W. C., Yao, T., & Kawaguchi, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030924 · Cited by 119 · see citing works
“Hdac6-deficient mice show emotional abnormalities Hdac6-deficient (KO) mice are viable and fertile, and develop normally, regardless of the hyperacetylation of a-tubulin in most tissues [5].”
BackgroundHDAC signaling in neuronal development and axon regeneration
Cho, Y., & Cavalli, V. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.03.008 · Cited by 136 · see citing works
Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production
Wang, B., Rao, Y.-H., Inoue, M., Hao, R., Lai, C.-H., Chen, D. J., McDonald, S. L., Choi, M.-C., Wang, Q., Shinohara, M. L., et al. (2014) · Nature Communications · doi:10.1038/ncomms4479 · Cited by 127 · see citing works
Development and Therapeutic Implications of Selective Histone Deacetylase 6 Inhibitors
Kalin, J. H., & Bergman, J. A. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4001659 · Cited by 129 · see citing works
Ageta‐Ishihara, N., Miyata, T., Ohshima, C., Watanabe, M., Sato, Y., Hamamura, Y., Higashiyama, T., Mazitschek, R., Bito, H., & Kinoshita, M. (2013) · Nature Communications · doi:10.1038/ncomms3532 · Cited by 130 · see citing works
Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension
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., et al. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.04.005 · Cited by 114 · see citing works
“In this regard, HDAC6 knockout mice are viable and fertile, and thus assessment of the response of these mice to increased ventricular afterload should be particularly enlightening [54].”
Razidlo, D. F., Whitney, T. J., Casper, M. E., McGee‐Lawrence, M. E., Stensgard, B. A., Li, X., Secreto, F. J., Knutson, S. K., Hiebert, S. W., & Westendorf, J. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011492 · Cited by 111 · see citing works
“Hdac6-deficiency modestly enhanced trabecular bone formation [15].”
BackgroundGodmann, M., Lambrot, R., & Kimmins, S. (2009) · Microscopy Research and Technique · doi:10.1002/jemt.20715 · Cited by 109 · see citing works
“Interestingly, genetic ablation of Hdac6, which shows the highest expression in the mouse testis, does not affect spermatogenesis as Hdac6 null mice are viable with normal fertility (Zhang et al., 2008).”
BackgroundYang, K., Wu, H., Zhang, Z., Leisten, E. D., Nie, X., Liu, B., Wen, Z., Zhang, J., Cunningham, M. D., & Tang, W. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00046 · Cited by 124 · see citing works
CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6
Yang, Y., Ran, J., Liu, M., Li, D., Li, Y., Shi, X., Meng, D., Pan, J., Ou, G., Aneja, R., et al. (2014) · Cell Research · doi:10.1038/cr.2014.136 · Cited by 115 · see citing works
Histone deacetylases: salesmen and customers in the post‐translational modification market
Brandl, A., Heinzel, T., & Krämer, O. H. (2009) · Biology of the Cell · doi:10.1042/bc20080158 · Cited by 107 · see citing works
The Biology of HDAC in Cancer: The Nuclear and Epigenetic Components
Hagelkrüys, A., Sawicka, A., Rennmayr, M., & Seiser, C. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-21631-2_2 · Cited by 111 · see citing works
Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition
Kalinski, A. L., Kar, A. N., Craver, J., Tosolini, A. P., Sleigh, J. N., Lee, S. J., Hawthorne, A. L., Brito‐Vargas, P., Miller-Randolph, S., Passino, R., et al. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201702187 · Cited by 119 · see citing works
Bobrowska, A., Paganetti, P., Matthias, P., & Bates, G. P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020696 · Cited by 110 · see citing works
“It has been previously reported that the Hdac6KO line of mice used in this study, has elevated levels of acetylated tubulin in peripheral tissue but not in brain [36].”
BackgroundMethodResultInfluentialSelf-citationGenetic dissection of histone deacetylase requirement in tumor cells
Haberland, M., Johnson, A., Mokalled, M. H., Montgomery, R. L., & Olson, E. N. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903139106 · Cited by 110 · see citing works
Histone deacetylases in skeletal development and bone mass maintenance
McGee‐Lawrence, M. E., & Westendorf, J. J. (2010) · Gene · doi:10.1016/j.gene.2010.12.003 · Cited by 112 · see citing works
“Germline Hdac6 deletion modestly increases trabecular bone mineral density via unknown mechanisms (Zhang et al., 2008).”
BackgroundHDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer
Fukumoto, T., Fatkhutdinov, N., Zundell, J. A., Tcyganov, E. N., Nacarelli, T., Karakashev, S. V., Wu, S., Liu, Q., Gabrilovich, D. I., & Zhang, R. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1302 · Cited by 124 · see citing works
“Notably, the complete genetic knockout of HDAC6 does not impair normal cell function (16).”
BackgroundThe role of microRNAs in bone remodeling
Jing, D., Hao, J., Shen, Y., Tang, G., Li, M., Huang, S.-H., & Zhao, Z. (2015) · International Journal of Oral Science · doi:10.1038/ijos.2015.22 · Cited by 106 · see citing works
Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models
Choi, H., Kim, H. J., Yang, J., Chae, S., Lee, W., Chung, S., Kim, J., Choi, H., Song, H., Lee, C. K., et al. (2019) · Aging Cell · doi:10.1111/acel.13081 · Cited by 122 · see citing works
“In HDAC6 KO MEFs, the basal levels of acetyl-αtubulin were highly increased as previously reported (Zhang et al., 2008) and CKD-504 did not affect the acetylation levels of both α-tubulin and histone.”
Background
- Authors
- Zhang, Y., Kwon, S., Yamaguchi, T., Cubizolles, F., Rousseaux, S., Kneissel, M., Cao, C., Li, N., Cheng, H.-L., Chua, K., Lombard, D., Mizeracki, A., Matthias, G., Alt, F. W., Khochbin, S., & Matthias, P.
- Affiliations
- Friedrich Miescher Institute (CH)
- Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, P.O. Box 2543, Maulbeerstrasse 66, 4058 Basel, Switzerland
- Inserm (FR)
- Novartis (Switzerland) (CH)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Matthias, Patrick
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-03-01
- Volume
- 28
- Issue
- 5
- Pages
- 1688-1701
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2258784
- OpenAlex
- W2162787110
- Cited by
- 559
- References
- 0
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 18 · 2023: 24 · 2022: 37 · 2021: 35 · 2020: 47 · 2019: 32 · 2018: 27 · 2017: 38 · 2016: 24 · 2015: 28 · 2014: 32 · 2013: 33 · 2012: 39
- FWCI
- 13.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- Dalhousie University
- Université de Fribourg
- Institut National Du Cancer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HDAC6, tubulin acetylation, tubulin deacetylation, alpha-tubulin, HSP90 acetylation, testicular development, lymphoid development, immune response, bone mineral density, microtubule organization, embryonic fibroblasts, post-translational modification, ubiquitin binding
- MeSH terms
- Histone Deacetylase 6, Acetylation, Animals, Cells, Cultured, Crosses, Genetic, Embryo, Mammalian, Female, Fetal Viability, Fibroblasts, Histone Deacetylases, Homozygote, Immunohistochemistry, Male, Mice, Inbred C57BL, Precipitin Tests, Pregnancy, Receptors, Glucocorticoid, Recombination, Genetic, Sperm Count, Spermatogenesis, Testis, Transfection, Tubulin, Absorptiometry, Photon, Bone Density, Gene Deletion, Genes, Reporter, Mice, Knockout, HSP90 Heat-Shock Proteins, Fluorescent Antibody Technique, Indirect, NIH 3T3 Cells, Embryonic Development, Luciferases, Renilla, Mice, Embryonic Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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