HDAC6: a key regulator of cytoskeleton, cell migration and cell–cell interactions

Valenzuela-Fernández, Agustı́n; Cabrero, José Román; Serrador, Juan Manuel; Sánchez-Madrid, Francisco

doi:10.1016/j.tcb.2008.04.003

Cited by 449 publications

(432 citation statements)

References 67 publications

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“…Interestingly, both HDAC5 and HDAC7 undergo active nucleocytoplasmic shuttling in response to extracellular signals (McKinsey et al, 2000;Vega et al, 2004), which may allow for fine-tuning of angiogenesis-related genes. In contrast, HDAC6 resides exclusively in the cytoplasm presumably due to its tetradecapeptide repeat domain and its association with cytoskeletal components (Bertos et al, 2004;Valenzuela-Fernández et al, 2008). Consistent with the localization pattern of HDAC6, it mainly participates in cytoskeleton-related activities, independently of histone modification (Boyault et al, 2007;Valenzuela-Fernández et al, 2008).…”

Section: Discussionmentioning

confidence: 59%

“…A number of HDAC inhibitors are in clinical development as anticancer agents (Xu et al, 2007), and one of them, suberoylanilide hydroxamic acid, has recently been approved for the treatment of advanced cutaneous T cell lymphoma (Marks, 2007). While most of the HDACs are localized in the nucleus, HDAC6 is a cytoplasmic protein associated with the cytoskeleton and involved in cytoskeleton-related activities (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). There is a growing body of evidence showing that HDAC6 functions at the intersection of the cytoskeleton and cell signaling to regulate cell motility, cell adhesion, and cell-cell interactions (Boyault et al, 2007;Valenzuela-Fernández et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…While most of the HDACs are localized in the nucleus, HDAC6 is a cytoplasmic protein associated with the cytoskeleton and involved in cytoskeleton-related activities (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). There is a growing body of evidence showing that HDAC6 functions at the intersection of the cytoskeleton and cell signaling to regulate cell motility, cell adhesion, and cell-cell interactions (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). These findings suggest that this deacetylase might have a role in angiogenesis, which is critically dependent on the aforementioned cellular activities (Lamalice et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Xie

Ren

et al. 2011

Protein Cell

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Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells. Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice. The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting. Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization. In addition, microtubule end binding protein 1 (EB1) is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures. These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Xie

Ren

et al. 2011

Protein Cell

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“…In addition to a-tubulin, several cytoplasmic proteins including Hsp90 [6,7], cortactin [8], b-catenin [9], peroxiredoxins I and II [10], and Ku70 [11] are regulated in a HDAC6-mediated deacetylation-dependent manner. Strong ubiquitin binding activity [12,13] further adds to the multifunctionality of HDAC6, enabling the regulation of many important processes including cell migration, cell stress response to the cytotoxic accumulation of protein aggregates, and immune synapse formation [1,2].…”

Section: Introductionmentioning

confidence: 99%

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

et al. 2012

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a b s t r a c tMitochondria perform multiple functions critical to the maintenance of cellular homeostasis. Here we report that the downregulation of histone deacetylase 6 (HDAC6) causes a reduction in the net activity of mitochondrial enzymes, including respiratory complex II and citrate synthase. HDAC6 deacetylase and ubiquitin-binding activities were both required for recovery of reduced mitochondrial metabolic activity due to the loss of HDAC6. Hsp90, a substrate of HDAC6, localizes to mitochondria and partly mediates the regulation of mitochondrial metabolic activity by HDAC6. Our finding suggests that HDAC6 regulates mitochondrial metabolism and might serve as a cellular homeostasis surveillance factor.

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“…Histone deacetylase 6 (HDAC6), a cytosolic member of class II HDACs 18 , is responsible for deacetylating both tubulin 19 and tau 16 . Intriguingly, neurons in which HDAC6 were knocked down lose the axonal initial segment (AIS) 20 , a trafficking barrier important for maintaining the polarized localization of axonal proteins, although the mechanism remains unknown.…”

mentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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HDAC6: a key regulator of cytoskeleton, cell migration and cell–cell interactions

Cited by 449 publications

References 67 publications

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

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