Histone Deacetylase  Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors

Federíco, M.; Bagella, Luigi

doi:10.1155/2011/475641

Cited by 84 publications

(60 citation statements)

References 98 publications

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“…Some of these inhibitors, so called epi-drugs, have been FDA approved for treatment of hematologic malignancies (37,38). Functioning genome-wide, however, these enzyme inhibitors are hardly predictable in terms of their effect in up-or downregulation of genes.…”

Section: Discussionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neu gene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu-overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.

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Section: Discussionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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“…Orally active and clinically well-tolerated broad inhibitors of histone deacetylases (HDACs), a class of enzymes that catalyse the deacetylation of cytosolic and nuclear proteins, including histones and transcription factors such as nuclear factor κB (NFκB) [5,6], have been developed for malignant disorders at high doses [7]. Recently, these compounds have shown promise in lower doses as potent and safe anti-inflammatory drugs in autoimmune diseases such as systemic-onset juvenile idiopathic arthritis [8].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

et al. 2012

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Aims/hypothesis Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. Methods The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. Results Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the proinflammatory mediators Il1α, Il1β, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. Conclusions/interpretation These data demonstrate nonredundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.

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“…Several HDAC and DNMT inhibitors are already available as putative anticancer drugs, and several clinical trials are underway [210,211].…”

Section: Discussionmentioning

confidence: 99%

Role of Enhancer of Zeste Homolog 2 Polycomb Protein and Its Significance in Tumor Progression and Cell Differentiation

Marchesi¹,

Bagella²

2013

Chromatin Remodelling

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Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors

Cited by 84 publications

References 98 publications

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

Role of Enhancer of Zeste Homolog 2 Polycomb Protein and Its Significance in Tumor Progression and Cell Differentiation

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