Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1α,25-dihydroxyvitamin D 3

Malinen, Marjo; Saramäki, Anna; Ropponen, Antti; Degenhardt, Tatjana; Vaïsänen, Sami; Carlberg, Carsten

doi:10.1093/nar/gkm913

Cited by 61 publications

(57 citation statements)

References 34 publications

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“…RNA Extraction and Real-time Quantitative PCR-Total RNA extraction and cDNA synthesis were performed as described previously (17). Real-time quantitative PCR for cDNA was performed using a LightCycler 480 System (Roche Applied Science) and FastStart SYBR Green Master mix (Roche Applied Science).…”

Section: Methodsmentioning

confidence: 99%

“…The p21 gene has been shown to respond to 1␣,25(OH) 2 D 3 in several mammary cell lines, including MDA-MB453 cells (17). To further elucidate the dynamics of p21 induction, we performed real-time quantitative PCR analysis of p21 mRNA expression in response to 1␣,25(OH) 2 D 3 in a detailed time course of 300 min with 15-min intervals (Fig.…”

Section: Cyclical Induction Of P21 Mrna Expression By 1␣25(oh) 2 D 3 -mentioning

confidence: 99%

“…1). On the chromatin templates we determined by real-time quantitative PCR the 1␣,25(OH) 2 D 3 -induced enrichment of the three previously identified VDR-associated regions (6,17) and the p21 TSS in comparison to that in untreated cells ( Fig. 2A).…”

Section: Cyclical Induction Of P21 Mrna Expression By 1␣25(oh) 2 D 3 -mentioning

confidence: 99%

“…S2). In addition to the factors studied in ChIP assays, we studied the effect of knock-down of VDR-linked cofactors, such as HDAC5 and HDAC7 (17), and the NCoR1 related co-repressor Silencing Mediator of Retinoid and Thyroid Receptors (SMRT, also called NCoR2) in combination with NCoR1 (Fig. S2).…”

Section: Med1 Lsd1 and Hdac4 Are Essential For The Cycling Of P21 Tmentioning

confidence: 99%

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Cyclical Chromatin Looping and Transcription Factor Association on the Regulatory Regions of the p21 (CDKN1A) Gene in Response to 1α,25-Dihydroxyvitamin D3

Saramäki

Diermeier

Kellner

et al. 2009

Journal of Biological Chemistry

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The nuclear receptor vitamin D receptor (VDR) is known to associate with three vitamin D response element (VDREs)-containing regions within the CDKN1A (p21) gene region. Here we show in MDA-MB453 breast cancer cells that the natural VDR ligand 1␣,25-dihydroxyvitamin D 3 causes cyclical transcription factor binding and chromatin looping of distal VDREs to the transcription start site (TSS) of the p21 gene, leading to cyclical accumulation of the p21 mRNA. At the chromatin level, association of the mediator protein MED1 precedes both the peaks of VDR binding to VDREs and phosphorylated RNA polymerase (p-Pol II) to the TSS. The loss of co-repressor NCoR1-histone deacetylase (HDAC) 3 complex and inhibitory chromatin looping from VDREs to the TSS are also initial events followed by increased acetylation of histone 3 at lysine 9 at the TSS prior to initiation of transcription. Simultaneous to VDR and p-Pol II peaks, chromatin loops between VDREs and the TSS are formed, and the lysine demethylase LSD1 and the histone acetyltransferase CBP are enriched in both regions. This is followed by a moderate peak in p21 transcript accumulation, repeated in cycles of 45-60 min. The transcript accumulation pattern is disturbed by siRNA inhibition of the mediator protein MED1, LSD1, NCoR1, or various HDACs, whereas CBP appears unnecessary for the response. Inhibition of MED1, HDAC4, or LSD1 by siRNA also attenuates ligand-induced chromatin looping. In conclusion, 1␣,25-dihydroxyvitamin D 3 regulates p21 transcription by inducing cyclical chromatin looping that depends on both histone deacetylation and demethylation.As a member of the nuclear receptor (NR) 2 superfamily the vitamin D receptor (VDR) acts as a transcription factor that binds to specific response elements (VDREs) within the regulatory regions of its primary target genes (1). The natural VDR ligand 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) has an important role in the regulation of calcium and phosphate homeostasis and bone mineralization (2). In addition to this classical role, there is both epidemiological and preclinical evidence that 1␣,25(OH) 2 D 3 is an anti-proliferative agent (3). Vitamin D deficiency increases the risk of certain cancers, whereas the administration of 1␣,25(OH) 2 D 3 in cell culture or in animal models for cancer inhibits angiogenesis and induces G0/G1 arrest, differentiation, and apoptosis (4). These antiproliferative effects are exerted by various 1␣,25(OH) 2 D 3 target genes, among which the product of cyclin-dependent kinase inhibitor 1A (CDKN1A, also called p21) gene induces G0/G1 cell cycle arrest and differentiation (5). We have previously characterized three functional VDREs residing 2-7-kb upstream of the TSS of p21 gene (6).Non-liganded VDR is associated with primary co-repressors, such as the nuclear receptor co-repressor (NCoR1), that attenuate transcription via interaction with histone deacetylases (HDACs) that pose the chromatin modifications unfavorable for transcription or, at least in the case of NCoR1, are also able to rec...

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Section: Methodsmentioning

confidence: 99%

Section: Cyclical Induction Of P21 Mrna Expression By 1␣25(oh) 2 D 3 -mentioning

confidence: 99%

Section: Cyclical Induction Of P21 Mrna Expression By 1␣25(oh) 2 D 3 -mentioning

confidence: 99%

Section: Med1 Lsd1 and Hdac4 Are Essential For The Cycling Of P21 Tmentioning

confidence: 99%

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Cyclical Chromatin Looping and Transcription Factor Association on the Regulatory Regions of the p21 (CDKN1A) Gene in Response to 1α,25-Dihydroxyvitamin D3

Saramäki

Diermeier

Kellner

et al. 2009

Journal of Biological Chemistry

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100

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“…This aspect may have some diagnostic and therapeutic value in different types of cancer [26]. However, the switch between gene repression and activation is more complex than a simple alternative recruitment of two different regulatory complexes [27]. Most co-regulators are co-expressed in the same cell type at relatively similar levels, which raises the possibility of their concomitant recruitment to a specific promoter.…”

Section: Nrs As Molecular Switchesmentioning

confidence: 99%

New Insights to Nuclear Receptor Gene Regulation from Analysis of their Response Elements in Target Genes

Carlberg

2010

Nuclear Receptors

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Abstract:Nuclear receptor (NR) target genes have key roles in cellular metabolism, cellular growth and differentiation and in controlling inflammation. Many NR target genes are also involved in dysregulated pathways that can lead to common human diseases, such as type 2 diabetes, atherosclerosis, Alzheimer's disease and cancer. On the genomic level these pathways converge on regulatory modules, some of which contain co-localizing NR binding sites, so-called response elements (REs). Recent advances in genomic techniques combined with computational analysis of binding modules are discussed in this chapter, primarily at the example of the NRs vitamin D receptor (VDR or NR1I1) and peroxisome proliferator-activated receptors (PPARα or NR1C1, PPARβ/δ or NR1C2 and PPARγ or NR1C3). 17

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Loss of NECL1, a novel tumor suppressor, can be restored in glioma by HDAC inhibitor‐Trichostatin A through Sp1 binding site

Gao

Chen

Liu

et al. 2008

Glia

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Nectin-like molecule 1 (NECL1)/CADM3/IGSF4B/TSLL1/SynCAM3 is a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule downregulated at the mRNA level in 12 human glioma cell lines. Here we found that the expression of NECL1 was lost in six glioma cell lines and 15 primary glioma tissues at both RNA and protein levels. Re-expression of NECL1 into glioma cell line U251 would repress cell proliferation in vitro by inducing cell cycle arrest. And also NECL1 could decrease the growth rate of tumors in nude mice in vivo. To further investigate the mechanism why NECL1 was silenced in glioma, the basic promoter region located at -271 to +81 in NECL1 genomic sequence was determined. DNA bisulfite sequencing was performed to study the methylation status of CpG islands in NECL1 promoter; however, no hypermethylated CpG site was found. Additionally, the activity of histone deacetylase (HDACs) in glioma was higher than that in normal brain tissues, and the expression of NECL1 in glioma cell lines could be reactivated by HDACs inhibitor-Trichostatin A (TSA). So the loss of NECL1 in glioma was at least partly caused by histone deacetylation. Luciferase reporter assays, chromatin immunoprecipitation and co-immunoprecipitation (co-IP) assays indicated that Sp1 played an important role in this process by binding to either HDAC1 in untreated glioma cells or p300/CBP in TSA treated cells. Our finding suggests that NECL1 may act as a tumor suppressor in glioma and loss of it in glioma may be caused by histone deacetylation.

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Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1α,25-dihydroxyvitamin D 3

Cited by 61 publications

References 34 publications

Cyclical Chromatin Looping and Transcription Factor Association on the Regulatory Regions of the p21 (CDKN1A) Gene in Response to 1α,25-Dihydroxyvitamin D3

Cyclical Chromatin Looping and Transcription Factor Association on the Regulatory Regions of the p21 (CDKN1A) Gene in Response to 1α,25-Dihydroxyvitamin D3

New Insights to Nuclear Receptor Gene Regulation from Analysis of their Response Elements in Target Genes

Loss of NECL1, a novel tumor suppressor, can be restored in glioma by HDAC inhibitor‐Trichostatin A through Sp1 binding site

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