Diversity in the Sir2 family of protein deacetylases

Buck, Stephen W.; Gallo, Christopher M.; Smith, Jeffrey S.

doi:10.1189/jlb.0903424

Cited by 93 publications

(79 citation statements)

References 126 publications

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“…21 Unlike the other class I and II HDACs, sirtuins require nicotinamide adenosine dinucleotide (NAD) as a cofactor, rather than zinc. 22 The mammalian sirtuin SIRT1 gene product encodes an NAD-dependent nuclear HDAC that is the closest structural ortholog of the yeast Sir2 protein. 23 SIRT1 regulates the activity of a variety of transcription factor and transcriptional coregulators such as p53, Ku70, NF-jB, MyoD, FOXO1, FOXO3a, PPARg and p300.…”

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confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

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Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-jB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: genistein; prostate cancer; tumor suppressor gene Genistein (4 0 ,5,7-trihydroxyflavone), a naturally occurring isoflavenoid abundant in soy products, has been identified as an inhibitor of protein tyrosine kinases, which play key roles in cell growth and apoptosis. 1,2 Genistein has been reported to have estrogenic properties and antineoplastic activity in multiple tumor types. 3 One mode by which hormonal agents work is by regulating gene activity by modulating epigenetic events such as histone acetylation and DNA methylation. 4,5 Genistein was also found to have epigenetic effects in the mouse prostate. 6 Taken together, these findings suggest that genistein's antitumor activity may be mediated by epigenetic-based pathways. On the other hand, genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-jB) pathway, which could be mediated via AKT (AKT8 virus oncogene cellular homolog) signaling, the most important survival pathway in cellular signaling. 7 However, the precise molecular mechanism has yet to be characterized.AKT is a serine/threonine protein kinase functioning downstream of phosphatidylinositol 3-kinase (PI3K) in response to mitogen or growth factor stimulation. High-levels of AKT activation have been associated with the development and metastasis of several cancers. 8 AKT activation not only directly inhibits apoptosis by multiple mechanisms involved in inhibiting the conformational change of Bax, BAD and caspase-9 but also modulates apoptosis indirectly by influencing the activities of several transcription factors, including fork head transcription factors (FOXO) and...

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confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

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“…They play an important role in epigenetic regulation of gene transcription and also control other cellular functions, such as proliferation, cell death, and motility (2). There are currently 18 known mammalian deacetylase enzymes which can be divided into two major groups: Zn 2+ -dependent HDACs (1, 2) and NAD + -dependent sirtuins (3,4). Zn 2+ -dependent HDACs can be further subdivided into three classes: class I, which is homologous to yeast Rpd3, includes HDAC1 (5), HDAC2 (6), HDAC3 (7), and HDAC8 (8,9); class II, which shows homology to yeast Hda1, includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 (10 -15); and HDAC11 (16) is the sole member of class IV HDACs.…”

Section: Introductionmentioning

confidence: 99%

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

Fournel¹,

Bonfils²,

Hou³

et al. 2008

Molecular Cancer Therapeutics

308

241

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Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotypeselective HDAC inhibitor. We have developed an isotypeselective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759 -68]

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“…Sir2 is the founding member of the conserved sirtuin deacetylase family (2), with Sir2 directing its activity toward lysine 16 of histone H4 (H4K16) to promote silent chromatin formation (reviewed in ref. 3). There is also evidence that deacetylation of lysine 56 of histone H3 (H3K56) by Sir2 (4), or the sirtuins Hst3 and Hst4 (5), enables silencing at the telomeres and HM loci.…”

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confidence: 99%

The glucanosyltransferase Gas1 functions in transcriptional silencing

Koch

Pillus

2009

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

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Transcriptional silencing is a crucial process that is mediated through chromatin structure. The histone deacetylase Sir2 silences genomic regions that include telomeres, ribosomal DNA (rDNA) and the cryptic mating-type loci. Here, we report an unsuspected role for the enzyme Gas1 in locus-specific transcriptional silencing. GAS1 encodes a ␤-1,3-glucanosyltransferase previously characterized for its role in cell wall biogenesis. In gas1 mutants, telomeric silencing is defective and rDNA silencing is enhanced. We show that the catalytic activity of Gas1 is required for normal silencing, and that Gas1's role in silencing is distinct from its role in cell wall biogenesis. Established hallmarks of silent chromatin, such as Sir2 and Sir3 binding, H4K16 deacetylation, and H3K56 deacetylation, appear unaffected in gas1 mutants. Thus, another event required for telomeric silencing must be influenced by GAS1. Because the catalytic activity of Gas1 is required for telomeric silencing, Gas1 localizes to the nuclear periphery, and Gas1 and Sir2 physically interact, we propose a model in which carbohydrate modification of chromatin components provides a new regulatory element that may be critical for chromatin function but which is virtually unexplored in the current landscape of chromatin analysis.acetylation ͉ beta-glucan ͉ chromatin ͉ S. cerevisiae ͉ telomeres T he formation of silent chromatin leads to the transcriptional repression of regions of the genome. In the yeast Saccharomyces cerevisiae, these regions include the telomeres, ribosomal DNA (rDNA), and the cryptic mating-type loci (the HM loci, HML, and HMR), all of which require the silent information regulator 2 protein (Sir2), an NAD ϩ -dependent protein deacetylase (reviewed in ref. 1). Sir2 is the founding member of the conserved sirtuin deacetylase family (2), with Sir2 directing its activity toward lysine 16 of histone H4 (H4K16) to promote silent chromatin formation (reviewed in ref.3). There is also evidence that deacetylation of lysine 56 of histone H3 (H3K56) by Sir2 (4), or the sirtuins Hst3 and Hst4 (5), enables silencing at the telomeres and HM loci. Sir2 functions in the SIR complex with Sir3 and Sir4 to silence at telomeres, and also at the HM loci, where an additional protein, Sir1, also participates (1). However, within the rDNA, the Sir2 containing RENT complex acts independently of the other Sir proteins (1). Distinctions among the 3 silenced regions led to the hypothesis that different mechanisms of silent chromatin formation and regulation exist for each region.The basic model for silent chromatin formation at telomeres and HM loci involves recruitment of the SIR complex by DNA binding proteins, followed by Sir2-mediated histone deacetylation and additional SIR complex spreading. Hypoacetylation of histones enables silent chromatin spreading in the absence of Sir2 deacetylase activity, but is not sufficient for full silencing (6). Instead, deacetylase activity must be targeted to the silenced loci through Sir3 or some other means (7). Although...

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Diversity in the Sir2 family of protein deacetylases

Cited by 93 publications

References 126 publications

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

The glucanosyltransferase Gas1 functions in transcriptional silencing

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