Epigenetic Regulation of Gelsolin Expression in Human Breast Cancer Cells

Mielnicki, Lawrence M.; Ying, Angela; Head, Karen; Asch, Harold L.; Asch, Bonnie B.

doi:10.1006/excr.1999.4461

Cited by 102 publications

(71 citation statements)

References 68 publications

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“…In some instances, HDACIs repress gene expression by an indirect mechanism that involves recruitment of a repressor protein rather than a transcriptional activator as a consequence of histone acetylation. [3][4][5][6][7][8][9][76][77][78] Treatment with HDACIs was found to repress the expression of cyclin D1, cyclin A, Bcl-2, vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1α. Besides histone acetylation, treatment with HDACIs was found to result in hyperacetylation of numerous non-histone proteins that are required for transcription, cell cycle, signal transduction, and other cellular functions.…”

Section: Anti-tumor Activity Of Hdacismentioning

confidence: 99%

Histone Deacetylase Inhibitors for Cancer Therapy

Kim¹,

Bang²,

Robertson³

2006

Epigenetics

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The epigenome of cancer cells is determined by DNA methylation and an array of post-translational modifications of the core histones. Epigenetic abnormalities are commonly found in human tumors and importantly, they can be reversed by pharmacologic inhibitors. Histone deacetylase inhibitors (HDACIs) represent one of the most promising epigenetic treatments for cancer. HDACIs have emerged as promising targets for cancer therapy because they reactivate the transcription of multiple genes that are silenced in human tumors and they show pleiotropic anti-tumor effects selectively in cancer cells. HDACIs are well-tolerated and several show promising anti-tumor activity. While gene transcription has been considered to be the major target of HDACIs, inhibition of acetylation of non-histone proteins is now emerging as a novel basis for their anti-tumor effects. In this review, we discuss new insights into the molecular mechanism of HDACIs, their current status of clinical development, and possible future uses in cancer therapy.

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Section: Anti-tumor Activity Of Hdacismentioning

confidence: 99%

Histone Deacetylase Inhibitors for Cancer Therapy

Kim¹,

Bang²,

Robertson³

2006

Epigenetics

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“…The action of FR on gp130 and STAT3 may account in part for the more prominent effect of FR in elevating the response to all IL-6 cytokines, including IL-6 (Table 1). The broader action of FR on the expression of genes known to be sensitive to inhibition of histone deacetylation became evident when measuring the two tumor suppressors, gelsolin and p21 (Figure 4a) (Chen et al, 2000;Mielnicki et al, 1999).…”

Section: Fr Treatment Induces Expression Of Il-6 Type Receptor Subunimentioning

confidence: 99%

FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins

et al. 2002

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The related members of the interleukin-6 (IL-6) family of cytokines, leukemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6 are inflammatory mediators that control differentiated cell functions as well as proliferation. The cellular responsiveness to these cytokines is largely determined by the expression of the appropriate receptor proteins. The receptor expression profile for each cell type is established during differentiation and is often altered during oncogenic transformation. Since inhibition of histone deacetylases (HDAC) has the potential to re-activate epigenetically silenced genes, we asked whether inhibition of HDAC enhances the expression of IL-6 cytokine receptors and, thus, increase desirable cytokine responses. We demonstrate that treatment with FR901228 (FR), an HDAC inhibitor, increases the responsiveness to LIF in different cell types, including normal fibroblasts, epithelial cells, macrophages and splenocytes, as well as various tumor cell lines. Depending on the cell type, FR treatment also enhances the responsiveness to OSM and IL-6. These effects involve a transcriptional induction of the cytokine receptor subunits LIFRa, OSMRb, gp130, or the transcription factor STAT3. FR-specific induction of LIFRa occurs independently of de novo protein synthesis and cell proliferation and is mediated in part by the CBP/p300 coactivator. Chromatin immunoprecipitation experiments indicate that the expression of LIFRa and gp130 genes correlates with the level of acetylated histone 3 associated with the receptor promoter regions. The FR-stimulated expression of IL-6-type cytokine receptors in certain tumor cells also provided improved conditions for suppression of cell growth by taking advantage of the growth inhibitory effect of these cytokines.

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“…In transformed cells, in addition to TMs, many other proteins including those associated with micro®laments are also suppressed. For example, expression of gelsolin, vinculin, a-actinin and caldesmon is downregulated in many transformed cells and tumors Ben-Ze'ev, 1997;Button et al, 1995;Janmey and Chaponnier, 1995;Mielnicki et al, 1999). Given the high degree of the malignant nature of DT cells, these changes are expected to be extensive.…”

Section: Expression Of Cytoskeletal Proteins In Tm1 Mediated Reversionmentioning

confidence: 99%

Cytoskeletal organization in tropomyosin-mediated reversion of ras-transformation: Evidence for Rho kinase pathway

et al. 2001

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Tropomyosin (TM) family of cytoskeletal proteins is implicated in stabilizing actin micro®laments. Many TM isoforms, including tropomyosin-1 (TM1), are downregulated in transformed cells. Previously we demonstrated that TM1 is a suppressor of the malignant transformation, and that TM1 reorganizes micro®la-ments in the transformed cells. To investigate how TM1 induces micro®lament organization in transformed cells, we utilized ras-transformed NIH3T3 (DT) cells, and those transduced to express TM1, and/or TM2. Enhanced expression of TM1 alone, but not TM2, results in re-emergence of micro®laments; TM1, together with TM2 remarkably improves micro®lament architecture. TM1 induced cytoskeletal reorganization involves an enhanced expression of caldesmon, but not vinculin, aactinin, or gelsolin. In addition, TM1-induced cytoskeletal reorganization and the revertant phenotype appears to involve re-activation of RhoA controlled pathways in DT cells. RhoA expression, which is suppressed in DT cells, is signi®cantly increased in TM1-expressing cells, without detectable changes in the expression of Rac or Cdc42. Furthermore, expression of a dominant negative Rho kinase, or treatment with Y-27632 disassembled micro®laments in normal NIH3T3 and in TM1 expressing cells. These data suggest that reactivation of Rho kinase directed pathways are critical for TM1-mediated micro®lament assemblies. Oncogene (2001) 20, 2112 ± 2121.

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Epigenetic Regulation of Gelsolin Expression in Human Breast Cancer Cells

Cited by 102 publications

References 68 publications

Histone Deacetylase Inhibitors for Cancer Therapy

Histone Deacetylase Inhibitors for Cancer Therapy

FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins

Cytoskeletal organization in tropomyosin-mediated reversion of ras-transformation: Evidence for Rho kinase pathway

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