Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Methot, Joey L.; Chakravarty, Prasun K.; Chénard, Mélissa; Close, Joshua; Cruz, Jonathan C.; Dahlberg, William K.; Fleming, James E.; Hamblett, Christopher L.; Hamill, Julie E.; Harrington, Paul E.; Harsch, Andreas; Heidebrecht, Richard W.; Hughes, Bethany; Jung, Joon; Kenific, Candia M.; Kral, Astrid M.; Meinke, Peter T.; Middleton, Richard E.; Ozerova, Nicole; Sloman, David L.; Stanton, Matthew; Szewczak, Alexander A.; Tyagarajan, Sriram; Witter, David J.; Secrist, J. Paul; Miller, Thomas A.

doi:10.1016/j.bmcl.2007.12.031

Cited by 166 publications

(165 citation statements)

References 22 publications

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“…1, C and D). We therefore examined the effects of selective HDAC inhibition on the TMEM16A expression level using three chemical compounds: an HDAC1 and HDAC2 selective HDACi, AATB (IC 50 5 0.007 and 0.049 mM for HDAC1 and HDAC2, respectively, and IC 50 .. 10 mM for the other HDAC isoforms) (Methot et al, 2008), an HDAC3 selective HDACi, T247 (IC 50 5 0.24 mM for HDAC3, IC 50 .. 100 mM for the other HDAC isoforms) , and an HDAC6 selective HDACi, NCT-14b (IC 50 5 0.082 mM for HDAC6, IC 50 . 3.5mM for the other HDAC isoforms) (Itoh et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

Downregulation of Ca²⁺-Activated Cl⁻ Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Matsuba

Niwa

Muraki

et al. 2014

J Pharmacol Exp Ther

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The Ca 21 -activated Cl 2 channel transmembrane proteins with unknown function 16 A (TMEM16A; also known as anoctamin 1 or discovered on gastrointestinal stromal tumor 1) plays an important role in facilitating the cell growth and metastasis of TMEM16A-expressing cancer cells. Histone deacetylase (HDAC) inhibitors (HDACi) are useful agents for cancer therapy, but it remains unclear whether ion channels are epigenetically regulated by them. Using real-time polymerase chain reaction, Western blot analysis, and whole-cell patch-clamp assays, we found a significant decrease in TMEM16A expression and its functional activity was induced by the vorinostat, a pan-HDACi in TMEM16A-expressing human cancer cell lines, the prostatic cancer cell line PC-3, and the breast cancer cell line YMB-1. TMEM16A downregulation was not induced by the chemotherapy drug paclitaxel in either cell

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Section: Resultsmentioning

confidence: 99%

Downregulation of Ca²⁺-Activated Cl⁻ Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Matsuba

Niwa

Muraki

et al. 2014

J Pharmacol Exp Ther

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“…In addition to the approved drug SAHA, we included other hydroxamic acid HDAC inhibitors: ITF-2357, PXD101, CRA-024781, and LBH-589, all currently in clinical development (13); the widely used tool compounds trichostatin A (TSA), scriptaid, and pyroxamide; and active SAHA analogs BRD-K17311666, BRD-K22912318, BRD-K90919562, and BRD-K92415738. Benzamides, containing an orthoamino anilide biasing element and thereby forming a chemically distinct class of HDAC inhibitors were represented by CI-994, MS-275, and MCGD-0103, which are all currently in clinical development, and by the research tool compounds BRD5298, BRD6929 (compound 60) (14), BRD9773, and BRD8451. Furthermore, cyclic peptide HDAC inhibitors apicidin and HC toxin and the ketone BRD-A94377914 (15) were included.…”

Section: Resultsmentioning

confidence: 99%

Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells

Kubicek

Gilbert²,

Fomina-Yadlin³

et al. 2012

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

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Under the instruction of cell-fate-determining, DNA-binding transcription factors, chromatin-modifying enzymes mediate and maintain cell states throughout development in multicellular organisms. Currently, small molecules modulating the activity of several classes of chromatin-modifying enzymes are available, including clinically approved histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors. We describe the genome-wide expression changes induced by 29 compounds targeting HDACs, DNMTs, histone lysine methyltransferases (HKMTs), and protein arginine methyltransferases (PRMTs) in pancreatic α-and β-cell lines. HDAC inhibitors regulate several hundred transcripts irrespective of the cell type, with distinct clusters of dissimilar activity for hydroxamic acids and orthoamino anilides. In contrast, compounds targeting histone methyltransferases modulate the expression of restricted gene sets in distinct cell types. For example, we find that G9a/GLP methyltransferase inhibitors selectively up-regulate the cholesterol biosynthetic pathway in pancreatic but not liver cells. These data suggest that, despite their conservation across the entire genome and in different cell types, chromatin pathways can be targeted to modulate the expression of selected transcripts.histone modification | gene regulation | chemical epigenetics | beta cell biology | cholesterol pathway E pigenetic mechanisms mediated through chromatin control cell-state and cell-type decisions during development and in the adult (1, 2). Chromatin-modifying enzymes have been shown to function by interacting with master transcription factors, regulating the expression of key target genes and conferring epigenetic memory through the propagation of modifications to the chromatin template. These modifications include methylation of the DNA itself and a variety of posttranslational modifications to histones, the proteins most closely interacting with DNA. Depending on the type of modification, e.g., acetylation or methylation, and the exact position of the modified amino acid, these modifications can activate or repress transcription of the underlying DNA sequence (3).Small molecules targeting chromatin have mainly been developed for the treatment of cancer, justified by the identification of genetic aberrations leading to overexpression or activation of several chromatin-modifying enzymes (4-7). In contrast to clinically approved HDAC and DNMT inhibitors, fewer compounds targeting histone lysine methyltransferases (HKMTs) and protein arginine methyltransferases (PRMTs) are available. These small molecules are mainly used as chemical probe compounds in basic research, and toxicity is often limiting for testing in animal models. Interestingly, for most of the 50 HKMTs and 30 histone demethylases encoded in the human genome, no specific compounds are available. Even for HDACs, most compounds inhibit HDACs 1, 2, 3, and 6 (8), and HDAC8-specific compounds are only now emerging (9).Chromatin-modifying enzymes play important roles in normal development,...

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“…In another approach, novel biaryl derivatives of benzamide inhibitors (SHI-1:2), which were designed based on homology modeling of HDAC1 and HDAC3, showed HDAC1/HDAC2-selective inhibitory activity. The SHI-1:2 inhibitors may access the internal cavity with dif- ferent shapes between HDAC1 and HDAC3 (Methot et al 2008). The first generation of clinical HDAC inhibitors was largely nonselective.…”

Section: Erasers Of Histone Acetylationmentioning

confidence: 99%

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

Seto

Yoshida

2014

Cold Spring Harbor Perspectives in Biology

1,498

1,212

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SUMMARYHistone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc-or NAD + -dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.

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Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Cited by 166 publications

References 22 publications

Downregulation of Ca²⁺-Activated Cl⁻ Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Downregulation of Ca²⁺-Activated Cl⁻ Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

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Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Cited by 166 publications

References 22 publications

Downregulation of Ca2+-Activated Cl− Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Downregulation of Ca2+-Activated Cl− Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

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Product

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Downregulation of Ca²⁺-Activated Cl⁻ Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Downregulation of Ca²⁺-Activated Cl⁻ Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells