Trichostatin A-induced histone acetylation causes decondensation of interphase chromatin

Tóth, Katalin; Knoch, Tobias; Wachsmuth, Malte; Frank-Stöhr, Monika; Stöhr, Michael; Bächer, Christian; Müller, Gabriele; Rippe, Karsten

doi:10.1242/jcs.01293

Cited by 218 publications

(192 citation statements)

References 68 publications

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“…Trichostatin A is a potent inhibitor of HDAC, and when added to cells, causes hyper-acetylation of histones (35). Exposure of CAG cells to 1 M concentration of trichostatin for 5 h significantly enhanced the expression of VEGF and MMP-9 in wild-type CAG cells (Fig.…”

Section: Restoration Of High Syndecan-1 Level In Nucleus Decreasesmentioning

confidence: 89%

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Purushothaman

Hurst

Pisano

et al. 2011

Journal of Biological Chemistry

102

116

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Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression (e.g. VEGF, MMP-9, hepatocyte growth factor (HGF), and RANKL). However, the mechanism whereby this enzyme regulates gene expression remains unknown. We previously reported that elevation of heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus. Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase (HAT) enzymes in vitro, we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of heparanase would result in increased HAT activity leading to stimulation of protein transcription. We found that myeloma cells or tumors expressing high levels of heparanase and low levels of nuclear syndecan-1 had significantly higher levels of HAT activity when compared with cells or tumors expressing low levels of heparanase. High levels of HAT activity in heparanase-high cells were blocked by SST0001, an inhibitor of heparanase. Restoration of high syndecan-1 levels in heparanase-high cells diminished nuclear HAT activity, establishing syndecan-1 as a potent inhibitor of HAT. Exposure of heparanase-high cells to anacardic acid, an inhibitor of HAT activity, significantly suppressed their expression of VEGF and MMP-9, two genes known to be up-regulated following elevation of heparanase. These results reveal a novel mechanistic pathway driven by heparanase expression, which leads to decreased nuclear syndecan-1, increased HAT activity, and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype.Heparanase, an endoglycosidase that cleaves heparan sulfate, is up-regulated in many cancers where it promotes tumor growth, angiogenesis, and metastasis (1, 2). High levels of heparanase in cancer patients are associated with shorter postoperative survival time compared with patients with low levels of heparanase (1). Although some of the tumor promoting effects of heparanase can be attributed to its ability to remodel the extracellular matrix barrier by cleaving heparan sulfate, heparanase is also known to regulate cell signaling and gene transcription (1, 3-5). Elevation of heparanase levels in myeloma cells, either by transfection of cells or by addition of recombinant active heparanase enzyme to cells, up-regulates expression of MMP-9, VEGF, HGF, 2 and RANKL, which together drive an aggressive tumor phenotype (6 -9). Although the mechanism whereby heparanase drives gene expression remains unknown, the enzyme is present and active in the nucleus where it could act locally to regulate gene expression (10).Acetylation of the N-terminal tails of histones by histone acetyltransferase enzymes has been known for many years to be a process correlating with transcriptional activation (11)(12)(13)(14). This process is balanced by the activity of histone deacetylases (HDACs), which selectivel...

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Section: Restoration Of High Syndecan-1 Level In Nucleus Decreasesmentioning

confidence: 89%

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Purushothaman

Hurst

Pisano

et al. 2011

Journal of Biological Chemistry

102

116

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“…Polyamines play a role in higher-order chromatin structure, and polyamine depletion alters chromatin structure in mammalian cells (30,42,43). HDAC inhibitors also induce global reorganization of chromatin structure (44). Therefore, changes in chromatin structure after polyamine depletion might be responsible for the altered response to HDAC inhibitors in polyaminedepleted cells.…”

Section: Discussionmentioning

confidence: 99%

Ornithine decarboxylase activity in tumor cell lines correlates with sensitivity to cell death induced by histone deacetylase inhibitors

Saunders

Verdin

2006

Molecular Cancer Therapeutics

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Inhibitors of histone deacetylases (HDAC) show significant promise as targeted anticancer agents against a variety of hematologic and solid tumors. HDAC inhibitors arrest the growth of primary cells, but they induce apoptosis or differentiation of tumor cells. Although the precise mechanism is unknown, differences in cell cycle checkpoints and chromatin structure may be responsible. Cellular polyamines regulate both cell cycle progression and chromatin structure. In tumors, polyamines are abundantly produced because of increased activity of the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase (ODC). To determine if polyamines contribute to the cellular response to HDAC inhibitors, we inhibited ODC activity with A-difluoromethylornithine. Polyamine depletion increased resistance to apoptosis induced by HDAC inhibitors. In addition, we found that ODC activity levels correlated with sensitivity to HDAC inhibitors in a panel of tumor cell lines. We conclude that polyamines participate in the cellular response to HDAC inhibitors and that ODC activity correlates with sensitivity to HDAC inhibitor -induced apoptosis. Thus, elevated polyamine levels might be a biomarker for tumor sensitivity to HDAC inhibitor -induced apoptosis. These findings warrant clinical evaluation of tumor samples to determine if high ODC activity levels predict sensitivity to HDAC inhibitors.

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“…TSA alters the epigenetic status of a cell directly, increasing histone acetylation and thus making regulatory regions more 'open' or accessible to transcription factors (Toth et al 2004, Durcova-Hills et al 2008. More specifically, treatment of gonadal germ cells with TSA has been shown to cause rapid downregulation of Prdm1 (the repressor of an overt pluripotency phenotype in germ cells) and to trigger germ cells to dedifferentiate or reprogramme into EGCs (Ancelin et al 2006, Durcova-Hills et al 2008.…”

Section: What Makes a 'Meiosis-competent' Germ Cell?mentioning

confidence: 99%

Sex determination in mammalian germ cells: extrinsic versus intrinsic factors

Bowles

Koopman²

2010

Reproduction

107

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Mammalian germ cells do not determine their sexual fate based on their XX or XY chromosomal constitution. Instead, sexual fate is dependent on the gonadal environment in which they develop. In a fetal testis, germ cells commit to the spermatogenic programme of development during fetal life, although they do not enter meiosis until puberty. In a fetal ovary, germ cells commit to oogenesis by entering prophase of meiosis I. Although it was believed previously that germ cells are pre-programmed to enter meiosis unless they are actively prevented from doing so, recent results indicate that meiosis is triggered by a signaling molecule, retinoic acid (RA). Meiosis is avoided in the fetal testis because a male-specifically expressed enzyme actively degrades RA during the critical time period. Additional extrinsic factors are likely to influence sexual fate of the germ cells, and in particular, we postulate that an additional male-specific fate-determining factor or factors is involved. The full complement of intrinsic factors that underlie the competence of gonadal germ cells to respond to RA and other extrinsic factors is yet to be defined.

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Trichostatin A-induced histone acetylation causes decondensation of interphase chromatin

Cited by 218 publications

References 68 publications

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Ornithine decarboxylase activity in tumor cell lines correlates with sensitivity to cell death induced by histone deacetylase inhibitors

Sex determination in mammalian germ cells: extrinsic versus intrinsic factors

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