Histone Deacetylase Inhibitor Trichostatin A Represses Estrogen Receptor α-Dependent Transcription and Promotes Proteasomal Degradation of Cyclin D1 in Human Breast Carcinoma Cell Lines

Alao, John P.; Lam, Eric W.‐F.; Ali, Simak; Buluwela, Laki; Bordogna, Walter; Lockey, Peter; Varshochi, Rana; Stavropoulou, Alexandra; Coombes, R. Charles; Vigushin, David M.

doi:10.1158/1078-0432.ccr-04-1023

Cited by 105 publications

(96 citation statements)

References 41 publications

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“…Collectively, these findings of down-regulation of growth-regulatory proteins suggest that sulforaphane may act as a HDAC inhibitor despite the lack of evidence for accumulation of global histone acetylation. The ability of sulforaphane to act as a HDAC inhibitor and down-regulate these proteins is consistent with previously published data indicating that the HDAC inhibitor trichostatin A down-regulates ER protein and the HDAC inhibitor LAQ824 down-regulates HER-2 protein through attenuation of mRNA levels and increased proteasomal degradation in human breast cancer cell lines (46,47).…”

Section: Discussionsupporting

confidence: 90%

Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines

Pledgie-Tracy

Sobolewski

Davidson

2007

Molecular Cancer Therapeutics

289

188

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Sulforaphane, an isothiocyanate found in cruciferous vegetables, has been shown to induce phase 2 detoxication enzymes and inhibit the growth of chemically induced mammary tumors in rats, although the exact mechanisms of action of sulforaphane are not understood. In this study, we evaluated the effects of sulforaphane on cell growth and death in several human breast cancer cell lines and examined the hypothesis that sulforaphane acts as a histone deacetylase (HDAC) inhibitor in these cell lines. Sulforaphane treatment inhibited cell growth, induced a G 2 -M cell cycle block, increased expression of cyclin B1, and induced oligonucleosomal DNA fragmentation in the four human breast cancer cell lines examined, MDA-MB-231, MDA-MB-468, MCF-7, and T47D cells. Activation of apoptosis by sulforaphane in MDA-MB-231 cells seemed to be initiated through induction of Fas ligand, which resulted in activation of caspase-8, caspase-3, and poly(ADPribose) polymerase, whereas apoptosis in the other breast cancer cell lines was initiated by decreased Bcl-2 expression, release of cytochrome c into the cytosol, activation of caspase-9 and caspase-3, but not caspase-8, and poly(ADP-ribose) polymerase cleavage. Sulforaphane inhibited HDAC activity and decreased the expression of estrogen receptor-A, epidermal growth factor receptor, and human epidermal growth factor receptor-2 in each cell line, although no change in the acetylation of H3 or H4 was seen. These data suggest that sulforaphane inhibits cell growth, activates apoptosis, inhibits HDAC activity, and decreases the expression of key proteins involved in breast cancer proliferation in human breast cancer cells. These results support testing sulforaphane in vivo and warrant future studies examining the clinical potential of sulforaphane in human breast cancer. [Mol Cancer Ther 2007;6(3):1013-21]

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Section: Discussionsupporting

confidence: 90%

Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines

Pledgie-Tracy

Sobolewski

Davidson

2007

Molecular Cancer Therapeutics

289

188

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“…We previously reported that TSA provokes clearance of ERa from the breast carcinoma cell line MCF-7 , extending a previous report that butyric acid may also induce removal of ERa from cells (Stevens et al, 1984). More recently, Alao et al (2004) also demonstrate that TSA represses ERa mRNA synthesis. A second type of deacetylase activity, the sirtuins, also exists.…”

Section: Introductionsupporting

confidence: 82%

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

et al. 2005

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Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-a (ERa), resulting in subsequent clearance of ERa protein from breast and ovarian cell lines. Inhibition of oestrogen signalling may account for the endocrine disorders, menstrual abnormalities, osteoporosis and weight gain that occur in a proportion of women treated with VPA for epilepsy or for bipolar mood disorder. Transcriptome profiling revealed that VPA and TSA also modulate the expression of, among others, key regulatory components of the cell cycle. Meta-analysis of genes directly responsive to oestrogen indicates that VPA and TSA have a generally antioestrogenic profile in ERa positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERa mRNA, indicating that a limited number of genes signal a hyperacetylated state within cells. Three members of the NAD-dependent deacetylases, the sirtuins, are upregulated by VPA and by TSA and sirtuin activity contributes to loss of ERa expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERa from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERa, pS2 and cyclin D1 promoters, by inducing recruitment of methyl cytosine binding protein 2 (MeCP2) with concomitant exclusion of the maintenance methylase DNMT1. Furthermore, we demonstrate that, in the presence of VPA, local DNA methylation, deacetylation and demethylation of activated histones and recruitment of inhibitory complexes occurs on the pS2 promoter.

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“…Our results showed that treatment of HepG2 cells with TSA facilitated IRF-1 degradation by the ubiquitin/proteasome pathway. Similar to our results, inhibition of HDAC activity by TSA also alters the function of several other important transcription factors, such as estrogen receptor a and steroidogenic factor 1, through targeting them for proteasomal degradation (45,46). CHIP was identified as an E3 ligase for IRF-1 as well as a number of HSP70-associated proteins, such as ErbB2 and PTEN (47,48); however, it was reported that CHIP acted as the chaperone for IRF-1 in unstressed cells.…”

Section: Discussionsupporting

confidence: 85%

Inhibition of Histone Deacetylase Activity Suppresses IFN-γ Induction of Tripartite Motif 22 via CHIP-Mediated Proteasomal Degradation of IRF-1

Gao

Wang

et al. 2013

The Journal of Immunology

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Tripartite motif (TRIM)22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor (IRF)-1 was crucial for basal and IFN-induced TRIM22 transcription via binding to a novel cis-element named 5′ extended IFN-stimulating response element. In this study, we investigated the role of histone deacetylase (HDAC) activity in TRIM22 induction by IFN-γ and its underlying mechanism. We found that the HDAC activity, especially that conferred by HDAC6, was required for IFN-γ–induced TRIM22 transcription. Importantly, inhibition of HDAC activity by trichostatin A (TSA) enhanced the hyperacetylation of heat shock protein (HSP)90 and suppressed its chaperone activity for IRF-1. Further study showed that TSA treatment promoted the proteasomal degradation of IRF-1 protein via enhancing the association of IRF-1 with the ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein. Moreover, carboxyl terminus of Hsc70-interacting protein was found to be involved in the TSA-mediated inhibitory effect on IFN-γ induction of TRIM22 as well as other IRF-1–dependent IFN-stimulated genes. This study may provide novel insight into the role of HDAC activity in the transcriptional control of IFN-stimulated gene induction.

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Histone Deacetylase Inhibitor Trichostatin A Represses Estrogen Receptor α-Dependent Transcription and Promotes Proteasomal Degradation of Cyclin D1 in Human Breast Carcinoma Cell Lines

Cited by 105 publications

References 41 publications

Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines

Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Inhibition of Histone Deacetylase Activity Suppresses IFN-γ Induction of Tripartite Motif 22 via CHIP-Mediated Proteasomal Degradation of IRF-1

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