Histone deacetylases as transducers and targets of nuclear signaling

Walkinshaw, Donald R.; Tahmasebi, Soroush; Bertos, Nicholas; Yang, Xiang-Jiao

doi:10.1002/jcb.21746

Cited by 38 publications

(31 citation statements)

References 86 publications

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“…Recent evidence suggests that class I HDACs may play important roles in modulating cellular survival (18). Genetic deletion of HDAC-1 in mice is embryonic lethal, and HDAC-2 knockout causes perinatal lethality due to cardiac defects (19,20).…”

Section: Discussionmentioning

confidence: 99%

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Lee

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

127

121

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Vascular endothelial cells (ECs) are exposed to different flow patterns (i.e., disturbed vs. laminar), and the associated oscillatory shear stress (OSS) or pulsatile shear stress (PSS) lead to differential responses. We investigated the roles of class I and II histone deacetylases (HDAC-1/2/3 and HDAC-5/7, respectively) in regulating NF-E2-related factor-2 (Nrf2) and Krüppel-like factor-2 (KLF2), two transcription factors governing many shear-responsive genes, and the cell cycle in ECs in response to OSS. Application of OSS (0.5 ± 4 dynes/cm 2 ) to cultured ECs sustainably up-regulated class I and II HDACs and their nuclear accumulation, whereas PSS (12 ± 4 dynes/cm 2 ) induced phosphorylation-dependent nuclear export of class II HDACs. En face immunohistochemical examination of rat aortic arch and experimentally stenosed abdominal aorta revealed high HDAC-2/3/5 levels in ECs in areas exposed to disturbed flow. OSS induced the association of HDAC-1/2/3 with Nrf2 and HDAC-3/ 5/7 with myocyte enhancer factor-2; deacetylation of these factors led to down-regulation of antioxidant gene NAD(P)H quinone oxidoreductase-1 (NQO1) and KLF2. HDAC-1/2/3-and HDAC-3/5/7-specific small interfering RNAs eliminated the OSS-induced downregulation of NQO1 and KLF2, respectively. OSS up-regulated cyclin A and down-regulated p21 CIP1 in ECs and induced their proliferation; these effects were mediated by HDAC-1/2/3. Intraperitoneal administration of the class I-specific HDAC inhibitor valproic acid into bromodeoxyuridine (BrdU)-infused rats inhibited the increased EC uptake of BrdU at poststenotic sites. The OSS-induced HDAC signaling and EC responses are mediated by phosphatidylinositol 3-kinase/Akt. Our findings demonstrate the important roles of different groups of HDACs in regulating the oxidative, inflammatory, and proliferative responses of ECs to disturbed flow with OSS.epigenetics | mechanotransduction | transcriptional regulation

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Section: Discussionmentioning

confidence: 99%

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Lee

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

127

121

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“…Sirtuins are involved in many biological processes including genome stability, cell cycle regulation and play critical roles in several metabolic pathways (for review, see [5]). The reader is referred to several excellent reviews discussing the classification and regulation of the different HDACs [6,7]. Here, we focus on summarizing what is known about class I HDACs, and, in particular, what has been learned from their genetic analysis in higher eukaryotes.…”

Section: Protein Deacetylasesmentioning

confidence: 99%

Multiple roles of class I HDACs in proliferation, differentiation, and development

Reichert

Choukrallah

Matthias

2012

Cell. Mol. Life Sci.

152

148

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Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the future.

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“…This SAR diverges from our previous observations on quinoline based mercaptoacetamides in which analogues containing five- carbon linkers proved more potent than those with four-carbon linkers. 6 Similar to quinoline, the indole caps also afforded potent and selective HDAC6 inhibitors, namely 7a, 7d, and 7e. Generally, the SAR indicates that substituents (isopropyl, chlorine) at the 3-position of the indole ring are not favorable for HDAC6 inhibition, as compounds 7b and 7c were much less potent than 7a.…”

mentioning

confidence: 99%

Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

Zhang

Bařinka

et al. 2017

ACS Med. Chem. Lett.

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A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC 50 , 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

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Histone deacetylases as transducers and targets of nuclear signaling

Cited by 38 publications

References 86 publications

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Multiple roles of class I HDACs in proliferation, differentiation, and development

Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

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