Detrimental Effect of Class-selective Histone Deacetylase Inhibitors during Tissue Regeneration following Hindlimb Ischemia

Spallotta, Francesco; Tardivo, Silvia; Nanni, Simona; Rosati, Jessica; Straino, Stefania; Mai, Antonello; Vecellio, Matteo; Capogrossi, Maurizio C.; Farsetti, Antonella; Martone, Julie; Bozzoni, Irene; Pontecorvi, Alfredo; Gaetano, Carlo; Colussi, Claudia

doi:10.1074/jbc.m113.484337

Cited by 29 publications

(18 citation statements)

References 41 publications

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“…Moreover, depending on their phosphorylation state, class IIa HDACs shuttle between the nucleus (dephosphorylated) and the cytoplasm (phosphorylated) [6]. Class IIa HDACs have a variety of nuclear and cytosolic targets, including MEF2 transcription factors, HIF1␣, STAT1, and fork-head box proteins [7] and are involved in diverse processes, such as cellular response to hypoxia [8], myogenesis [9], synaptic plasticity and memory formation [10], and tissue regeneration [11].…”

Section: Clinical Relevancementioning

confidence: 99%

Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells

Colarossi

Memeo²,

Colarossi³

et al. 2014

Proteomics Clinical Apps

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Section: Clinical Relevancementioning

confidence: 99%

Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells

Colarossi

Memeo²,

Colarossi³

et al. 2014

Proteomics Clinical Apps

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“…Because 48 hours of exposure damaged approximately 50% of cells, this time point was chosen for all experiments unless stated otherwise. To investigate the role of a specific class of HDACs involved in A1254-induced toxicity, cells were treated with the class I HDAC inhibitor MS-275 (Lanzillotta et al, 2013;Guida et al, 2014) and the class II HDAC inhibitor MC-1568 (Nebbioso et al, 2010;Spallotta et al, 2013;Guida et al, 2014) at 0.05, 0.5, and 5 mM. MTT assays showed that cell viability significantly improved in a dose-dependent manner when cells were pretreated with MS-275, as opposed to cells exposed to A1254 alone (Fig.…”

Section: Resultsmentioning

confidence: 99%

MS-275 Inhibits Aroclor 1254–Induced SH-SY5Y Neuronal Cell Toxicity by Preventing the Formation of the HDAC3/REST Complex on the Synapsin-1 Promoter

Formisano

Guida

Laudati

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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Polychlorinated biphenyl (PCB) exposure has been associated with neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, and dementia. Neuronal death elicited by the PCB mixture Aroclor 1254 (A1254) has been attributed to an increase in RE-1-silencing transcription factor (REST), which, in turn, correlates with a decrease in the synapsin-1 promoter gene. Although histone deacetylase (HDAC) inhibitors are known to be neuroprotective in several neurologic disorders, the core mechanisms governing this effect are not yet understood. Here, to examine howinhibitors prevent A1254-induced neuronal cell death, we exposed SH-SY5Y neuroblastoma cells to A1254. Exposure to A1254 (30.6 mM) for 24 and 48 hours resulted in a time-dependent cell death. Indeed, after 48 hours, MS-275, but not MC-1568, reverted A1254-induced cell death in a dose-dependent manner. Furthermore, A1254 significantly increased HDAC3, but not HDAC1 or HDAC2. Interestingly, REST physically interacted with HDAC3 after A1254 exposure. Chromatin immunoprecipitation assays revealed that MS-275 reverted the increased levels of HDAC3 binding and decreased acetylation of histone H3 within the synapsin-1 promoter region, thus reverting synapsin-1 mRNA reduction. Moreover, REST knockdown by small interfering RNA (siRNA) prevented HDAC3 from binding to the synapsin-1 promoter. Likewise, HDAC3 siRNA significantly reduced A1254-induced cell toxicity in SH-SY5Y cells and cortical neurons. Hence, this study demonstrates that inhibition of HDAC class I attenuates A1254-induced neuronal cell death by preventing HDAC3 binding and histone deacetylation within the synapsin-1 promoter region.

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“…It was reported in a mouse model of hindlimb ischaemia that the inhibition of class IIa HDACs is pro-angiogenic while class I HDAC inhibition is anti-angiogenic in mouse models of hindlimb ischemia [75].…”

Section: Peripheral Artery Diseasementioning

confidence: 99%

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

Moraga¹,

Lao²,

Zeng³

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Cardiovascular diseases (CVD) continue to be the leading cause of death in the world despite recent therapeutic advances. Although many CVDs remain incurable, enormous eforts have been placed in harnessing angiogenesis as therapeutics for these diseases. Epigenetics, the modiication of gene expression post-transcriptionally and post-translationally, are important in regulating many biological processes. One of the main post-translational epigenetic modiications, modiication of chromatin structure by the acetylation of histone tails within the chromatin by either histone deacetylases (HDACs) or histone acetyltransferases (HATs), is important in modulating gene transcription and has emerged as an important regulatory player from pathogenesis to therapeutics in CVDs. Particularly, HDACs, which are largely involved in promoting chromatin compaction and hence inhibitions of gene transcription, have been implicated in the pathogenic signalling underlying many aspects of CVDs. Recently, histone modiications have been demonstrated to play important roles in the angiogenesis process. Pharmacological inhibitions of HDACs have displayed promising therapeutic potentials in several pre-clinical models of CVDs where angiogenesis is of paramount importance. There are many evidences proving that pro-and anti-angiogenic therapies-and the impact of epigenetics in these processes-can help to artiicially reconstruct the vasculature in patients with cardiovascular diseases. Conversely, utilising knowledge of HDACs in angiogenesis might help to develop anti-angiogenic therapies in tackling diseases that are characterised with excessive pathological angiogenesis, including cancer and age-related macular degeneration. Understanding the molecular mechanisms underlying HDACs in modulating angiogenesis will undoubtedly beneit future therapeutics development. This chapter focuses on the emerging role of HDACs in angiogenesis and discuss their potentials and challenges in utilising HDAC inhibitors as therapeutics in several major cardiovascular diseases.

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Detrimental Effect of Class-selective Histone Deacetylase Inhibitors during Tissue Regeneration following Hindlimb Ischemia

Cited by 29 publications

References 41 publications

Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells

Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells

MS-275 Inhibits Aroclor 1254–Induced SH-SY5Y Neuronal Cell Toxicity by Preventing the Formation of the HDAC3/REST Complex on the Synapsin-1 Promoter

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

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