Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.

Yoshida, Minoru; Kijima, Masako; Akita, Motomu; Beppu, Teruhiko

doi:10.1016/s0021-9258(17)44885-x

Cited by 1,664 publications

(233 citation statements)

References 39 publications

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“…Deacetylation of the substrate was suppressed by adding 275 nM of the potent HDAC inhibitor trichostatin A. 25 Linear regression led to the following equations: f(x) = 33,210 x + 1026 (MAL), f(x) = 30,970 x + 5350 (MAL and NDA), f(x) = 29,640 x + 8322 (MAL, ML, and NDA), f(x) = 28,770 x + 1570 (MAL and inhibited enzyme), f(x) = 26,930 x + 445 (MAL, inhibited enzyme, and NDA), and f(x) = 26,960 x + 5620 (MAL, inhibited enzyme, ML, and NDA). Although there are some deviations between the different linear equations, the differences are not statistically significant (t-test).…”

Section: Resultsmentioning

confidence: 99%

A Homogeneous Nonisotopic Histone Deacetylase Activity Assay

Heltweg¹,

Jung²

2003

SLAS Discovery

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Histone deacetylases (HDACs) are important regulators of transcription, and their inhibitors are a promising class of anticancer agents. The methods for the determination of HDAC activity and its inhibition that are currently available suffer from various drawbacks, such as animal testing, radioactive substrates, or limited throughput. Therefore, a fast nonisotopic method for the measurement of HDAC activity is highly desirable. The authors present such an assay that relies on the fluorescent HDAC substrate developed previously in their group. After incubation of the substrate with the enzyme, a derivatization leads to efficient fluorescence quenching in the deacetylated metabolite. Thus, only the fluorescence emitted by the remaining substrate is detected, which allows for a convenient detection of HDAC activity in a homogeneous format that can be performed on multiwell plate readers. This procedure, called HDASH (histone deacetylase assay—homogeneous), should be a valuable tool in transcriptional research and especially drug discovery. ( Journal of Biomolecular Screening 2003:89-95)

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Section: Resultsmentioning

confidence: 99%

A Homogeneous Nonisotopic Histone Deacetylase Activity Assay

Heltweg¹,

Jung²

2003

SLAS Discovery

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“…HDACs are subdivided into two protein subfamilies, which differ in protein structure and mechanism of action: the classical HDAC family and the sirtuins family [103]. The pharmacological compounds SRT1720 and EX-527 were designed to inhibit sirtuins [84,90], whereas sodium butyrate [104], Trichostatin A [85], valproic acid [105], and D-βhydroxybutyrate [101] inhibit the classic HDACs. Given that the same intergenerational effects were obtained with compounds that interfere with different subfamilies of HDACs, which may also have different target proteins, these results would suggest that the effects are not direct.…”

Section: Discussionmentioning

confidence: 99%

“…Energy-sensing pathways have been implicated in the regulation of acetylation of histones, histone modifiers, and cellular proteins [82]. To test if modulation of acetylation levels causes changes in sexual morph ratios, we induced hyperacetylation by treating A. freiburgensis hermaphrodites with the histone deacetylase inhibitors SRT1720 [83,84], Trichostatin A [85], valproic acid [86,87], D-β-hydroxybutyrate [88], sodium butyrate [89], and EX-527 [90]. In all cases, more hermaphrodites than females were produced relative to control (Fig.…”

Section: Changes In the Maternal Histone Acetylation Status Correlate With Changes In F1 Development And Mode Of Reproductionmentioning

confidence: 99%

Parental energy-sensing pathways control intergenerational offspring sex determination in the nematode Auanema freiburgensis

et al. 2021

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Background Environmental stimuli experienced by the parental generation influence the phenotype of subsequent generations (Demoinet et al., Proc Natl Acad Sci U S A 114:E2689-E2698, 2017; Burton et al., Nat Cell Biol 19:252–257, 2017; Agrawal et al., Nature 401:60-63, 1999). The effects of these stimuli on the parental generation may be passed through the germline, but the mechanisms at the basis of this non-Mendelian type of inheritance, their level of conservation, how they lead to adaptive vs non-adaptive, and intergenerational vs transgenerational inheritance are poorly understood. Here we show that modulation of nutrient-sensing pathways in the parental generation of the nematode Auanema freiburgensis regulates phenotypic plasticity of its offspring. Results In response to con-specific pheromones indicative of stress, AMP-activated protein kinase (AMPK), mechanistic target of rapamycin complex 1 (mTORC1), and insulin signaling regulate stress resistance and sex determination across one generation, and these effects can be mimicked by pathway modulators. The effectors of these pathways are closely associated with the chromatin, and their regulation affects the chromatin acetylation status in the germline. Conclusion These results suggest that highly conserved metabolic sensors regulate phenotypic plasticity through regulation of subcellular localization of their effectors, leading to changes in chromatin acetylation and epigenetic status of the germline.

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“…87,88 The first discovered HDACI was trichrostatin A (TSA), identified from nature sources. 89 Since then, numerous natural HDACI products have been obtained from microbes, dietary plants, and medicinal plants. 90 HDACIs have emerged as a new class of anticancer drugs; a series of HDACIs have been synthesized and the number of HDACIs is constantly being updated.…”

Section: Hdacismentioning

confidence: 99%

HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis

Lyu

Peng

et al. 2019

Therapeutic Advances in Chronic Disease

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Fibrosis usually results from dysregulated wound repair and is characterized by excessive scar tissue. It is a complex process with unclear mechanisms. Accumulating evidence indicates that epigenetic alterations, including histone acetylation, play a pivotal role in this process. Histone acetylation is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are enzymes that remove the acetyl groups from both histone and nonhistone proteins. Aberrant HDAC activities are observed in fibrotic diseases, including cardiac and pulmonary fibrosis. HDAC inhibitors (HDACIs) are molecules that block HDAC functions. HDACIs have been studied extensively in a variety of tumors. Currently, there are four HDACIs approved by the US Food and Drug Administration for cancer treatment yet none for fibrotic diseases. Emerging evidence from in vitro and in vivo preclinical studies has presented beneficial effects of HDACIs in preventing or reversing fibrogenesis. In this review, we summarize the latest findings of the roles of HDACs in the pathogenesis of cardiac and pulmonary fibrosis and highlight the potential applications of HDACIs in these two fibrotic diseases.

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Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.

Cited by 1,664 publications

References 39 publications

A Homogeneous Nonisotopic Histone Deacetylase Activity Assay

A Homogeneous Nonisotopic Histone Deacetylase Activity Assay

Parental energy-sensing pathways control intergenerational offspring sex determination in the nematode Auanema freiburgensis

HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis

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