Histone Deacetylase 7 Associates with Hypoxia-inducible Factor 1α and Increases Transcriptional Activity

Kato, Hiroyuki; Tamamizu-Kato, Shiori; Shibasaki, Futoshi

doi:10.1074/jbc.m406320200

Cited by 188 publications

(168 citation statements)

References 41 publications

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“…HDAC-7 -/-mouse embryos display defects in the development and integrity of blood vessels (38). Moreover, HDAC-7 protein has been implicated in several biologic processes, including regulation of gene expression, either as coactivator or corepressor (39,40), and it plays a role in T cell differentiation by inducing Nur-related protein 77 (35).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Hemmatazad¹,

Rodrigues²,

Maurer³

et al. 2009

Arthritis & Rheumatism

102

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Objective. We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function.Methods. Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor ␤. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA.Results. SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression.Conclusion. Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Hemmatazad¹,

Rodrigues²,

Maurer³

et al. 2009

Arthritis & Rheumatism

102

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“…This repression occurs due to the targeting of HIF-1a/p300 complex by HDACi. HDACi could also decrease HIF-1a activation by inhibiting HDAC7 activity, since under hypoxic conditions, HDAC7 translocates to the nucleus, where it can interact with HIF-1a and increase its transcriptional activity (Kato et al, 2004).…”

Section: Hdaci Inhibits Angiogenesismentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…Heat shock stimulation induced HDAC4 nuclear translocation (Dai et al, 2005), hypoxic conditions, in the presence of HIF-1a, drive HDAC7 to the nucleus (Kato et al, 2004) and hormone occupancy of the AR induces nuclear transfer of HDAC7 and -4 (Halkidou et al, 2004;Karvonen et al, 2006). The mechanism by which these signals lead to class IIa HDACs nuclear accumulation is not known and undoubtedly deserves further investigation.…”

Section: Signalingmentioning

confidence: 99%

“…Supporting this in the case of class IIa HDACs, the C terminus of HDAC4 and -7 but not HDAC5 has been shown to bind to hypoxia-inducible factor 1a (HIF-1a), a transcription factor that controls expression of genes responsive to low oxygen tension. Surprisingly, association with HDAC7 leads to increased HIF-1a transcriptional activity under hypoxic conditions (Kato et al, 2004). The exact mechanism underlying the transcriptional activation of HIF-1a by some members of class IIa HDACs remained unclear until recently, when it was reported that inhibition of HDAC4 by small interfering RNA had a positive effect on HIF-1a acetylation, which correlated with reduced stability (Qian et al, 2006).…”

Section: Atypical Rolesmentioning

confidence: 99%