HDAC6: Physiological function and its selective inhibitors for cancer treatment

Yang, Penghui; Zhang, Lei; Zhang, Yingjie; Zhang, Jian; Xu, Wenfang

doi:10.5582/ddt.2013.v7.6.233

Cited by 44 publications

(37 citation statements)

References 52 publications

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“…Furthermore, expression of an oncogenic form of PDGFR-α found in gastrointestinal tumours is linked to cilium disassembly through Aurora A activation 82 . Therefore, inhibitors of these kinases could be useful for the treatment of both tumours and ciliopathies 92 .…”

Section: A Role For the Cilium In Cell Cycle Control And Human Cancermentioning

confidence: 99%

Cilium assembly and disassembly

2016

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The primary cilium is an antenna-like, immotile organelle present on most types of mammalian cells, which interprets extracellular signals that regulate growth and development. Although once considered a vestigial organelle, the primary cilium is now the focus of considerable interest. We now know that ciliary defects lead to a panoply of human diseases, termed ciliopathies, and the loss of this organelle may be an early signature event during oncogenic transformation. Ciliopathies include numerous seemingly unrelated developmental syndromes, with involvement of the retina, kidney, liver, pancreas, skeletal system and brain. Recent studies have begun to clarify the key mechanisms that link cilium assembly and disassembly to the cell cycle, and suggest new possibilities for therapeutic intervention.

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Section: A Role For the Cilium In Cell Cycle Control And Human Cancermentioning

confidence: 99%

Cilium assembly and disassembly

2016

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“…Eukaryotic protein deacetylases comprise two families: 11 classical histone deacetylases (HDACs) [83] and 7 sirtuins [84]. Although HDAC6 is the primary α-tubulin deacetylase in non-dividing cells [85], it has other substrates that may not be related to its effects on tubulin, such as Hsp90, cortactin, β-catenin, and periredoxins. HDAC6 also interacts with ubiquitin independent of its acetylase activity [86], suggesting a role in responding to protein aggregates and other stressors [87].…”

Section: Acetylation and Deacetylation Of Tubulinsmentioning

confidence: 99%

“…HDAC6 also interacts with ubiquitin independent of its acetylase activity [86], suggesting a role in responding to protein aggregates and other stressors [87]. Thus, manipulations of HDAC6 levels or activity may affect multiple pathways [83-85]. However, while nuclear HDAC knockouts are embryonic or perinatal lethal [83], HDAC6 null mice are viable and develop normally, albeit with hyperacetylated tubulin [88].…”

Section: Acetylation and Deacetylation Of Tubulinsmentioning

confidence: 99%

Post-translational modifications of tubulin: pathways to functional diversity of microtubules

Song

Brady

2015

Trends in Cell Biology

331

305

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Tubulin and microtubules are subject to a remarkable number of posttranslational modifications. Understanding the roles these modifications play in determining functions and properties of microtubules has presented a major challenge that is only now being met. Many of these modifications are found concurrently, leading to considerable diversity in cellular microtubules, which varies with development, differentiation, cell compartment and cell cycle. We now know that posttranslational modifications of tubulin affect not only the dynamics of the microtubules, but also their organization and interaction with other cellular components. Many early suggestions of how posttranslational modifications affect microtubules have been replaced with new ideas and even new modifications as our understanding of cellular microtubule diversity comes into focus.

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“…Microtubule dynamics are regulated by MAPs (e.g., MAP4 and stathmin) and are closely associated with post-translational modifications; in particular, α-tubulin acetylation is recognized as a well-known maker of stable microtubules and is governed by HDAC6 (Howell et al, 1999; Matsuyama et al, 2002; Perdiz et al, 2011; Yang et al, 2013; Akhmanova and Steinmetz, 2015; Alfaro-Aco and Petry, 2015; Kadavath et al, 2015). To clarify RABV-induced microtubule depolymerization, we next examined the expression levels of MAP4, stathmin, HDAC6 and its substrate, acetylated α-tubulin (ace-tubulin) in RABV-infected or mock-infected N2a cells at 24 and 48 hpi.…”

Section: Resultsmentioning

confidence: 99%

“…Among these modifications, the acetylation which occurs on lysine 40 of α-tubulin is fairly common and considered to be a well-known marker of stable microtubules (L'Hernault and Rosenbaum, 1985; Perdiz et al, 2011). Furthermore, α-tubulin can be deacetylated by histone deacetylase 6 (HDAC6), a primary α-tubulin deacetylase (Matsuyama et al, 2002; Yang et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Rabies Virus Infection Induces Microtubule Depolymerization to Facilitate Viral RNA Synthesis by Upregulating HDAC6

Zan

Liu

Sun

et al. 2017

Front. Cell. Infect. Microbiol.

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Rabies virus (RABV) is the cause of rabies, and is associated with severe neurological symptoms, high mortality rate, and a serious threat to human health. Although cellular tubulin has recently been identified to be incorporated into RABV particles, the effects of RABV infection on the microtubule cytoskeleton remain poorly understood. In this study, we show that RABV infection induces microtubule depolymerization as observed by confocal microscopy, which is closely associated with the formation of the filamentous network of the RABV M protein. Depolymerization of microtubules significantly increases viral RNA synthesis, while the polymerization of microtubules notably inhibits viral RNA synthesis and prevents the viral M protein from inducing the formation of the filamentous network. Furthermore, the histone deacetylase 6 (HDAC6) expression level progressively increases during RABV infection, and the inhibition of HDAC6 deacetylase activity significantly decreases viral RNA synthesis. In addition, the expression of viral M protein alone was found to significantly upregulate HDAC6 expression, leading to a substantial reduction in its substrate, acetylated α-tubulin, eventually resulting in microtubule depolymerization. These results demonstrate that HDAC6 plays a positive role in viral transcription and replication by inducing microtubule depolymerization during RABV infection.

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HDAC6: Physiological function and its selective inhibitors for cancer treatment

Cited by 44 publications

References 52 publications

Cilium assembly and disassembly

Cilium assembly and disassembly

Post-translational modifications of tubulin: pathways to functional diversity of microtubules

Rabies Virus Infection Induces Microtubule Depolymerization to Facilitate Viral RNA Synthesis by Upregulating HDAC6

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