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不同的组蛋白去乙酰化酶调节人类细胞周期蛋白依赖性激酶抑制基因对曲古抑菌素A和1α,25-二羟基维生素D3的转录反应。

Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to Trichostatin A and 1alpha,25-dihydroxyvitamin D3.

作者信息

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

机构信息

Department of Biochemistry, University of Kuopio, FIN-70211 Kuopio, Finland.

出版信息

Nucleic Acids Res. 2008 Jan;36(1):121-32. doi: 10.1093/nar/gkm913. Epub 2007 Nov 13.

DOI:10.1093/nar/gkm913
PMID:17999998
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2248733/
Abstract

The anti-proliferative effects of histone deacetylase (HDAC) inhibitors and 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] converge via the interaction of un-liganded vitamin D receptor (VDR) with co-repressors recruiting multiprotein complexes containing HDACs and via the induction of cyclin-dependent kinase inhibitor (CDKI) genes of the INK4 and Cip/Kip family. We investigated the effects of the HDAC inhibitor Trichostatin A (TSA) and 1alpha,25(OH)2D3 on the proliferation and CDKI gene expression in malignant and non-malignant mammary epithelial cell lines. TSA induced the INK4-family genes p18 and p19, whereas the Cip/Kip family gene p21 was stimulated by 1alpha,25(OH)2D3. Chromatin immunoprecipitation and RNA inhibition assays showed that the co-repressor NCoR1 and some HDAC family members complexed un-liganded VDR and repressed the basal level of CDKI genes, but their role in regulating CDKI gene expression by TSA and 1alpha,25(OH)2D3 were contrary. HDAC3 and HDAC7 attenuated 1alpha,25(OH)2D3-dependent induction of the p21 gene, for which NCoR1 is essential. In contrast, TSA-mediated induction of the p18 gene was dependent on HDAC3 and HDAC4, but was opposed by NCoR1 and un-liganded VDR. This suggests that the attenuation of the response to TSA by NCoR1 or that to 1alpha,25(OH)2D3 by HDACs can be overcome by their combined application achieving maximal induction of anti-proliferative target genes.

摘要

组蛋白脱乙酰酶（HDAC）抑制剂和1α,25 - 二羟基维生素D3 [1α,25(OH)2D3] 的抗增殖作用通过未结合配体的维生素D受体（VDR）与募集含有HDAC的多蛋白复合物的共抑制因子相互作用，以及通过诱导INK4和Cip/Kip家族的细胞周期蛋白依赖性激酶抑制剂（CDKI）基因而趋同。我们研究了HDAC抑制剂曲古抑菌素A（TSA）和1α,25(OH)2D3对恶性和非恶性乳腺上皮细胞系增殖及CDKI基因表达的影响。TSA诱导INK4家族基因p18和p19，而Cip/Kip家族基因p21则由1α,25(OH)2D3刺激。染色质免疫沉淀和RNA抑制试验表明，共抑制因子NCoR1和一些HDAC家族成员与未结合配体的VDR结合并抑制CDKI基因的基础水平，但其在TSA和1α,25(OH)2D3调节CDKI基因表达中的作用相反。HDAC3和HDAC7减弱了1α,25(OH)2D3依赖性的p21基因诱导，而NCoR1对此至关重要。相反，TSA介导的p18基因诱导依赖于HDAC3和HDAC4，但受到NCoR1和未结合配体的VDR的抑制。这表明，NCoR1对TSA反应的减弱或HDACs对1α,25(OH)2D3反应可以通过联合应用来克服，从而实现抗增殖靶基因的最大诱导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/98a0f4661621/gkm913f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/50c111ff66cd/gkm913f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/93926eaa5efe/gkm913f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/875bb8f2599b/gkm913f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/98a0f4661621/gkm913f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/50c111ff66cd/gkm913f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/93926eaa5efe/gkm913f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/875bb8f2599b/gkm913f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8373/2248733/98a0f4661621/gkm913f4.jpg

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