Upregulation and nuclear recruitment of HDACI in hormone refractory prostate cancer
Upregulation and nuclear recruitment of HDACI in hormone refractory prostate cancer
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DOI：
10.1002/pros.20022
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发表时间：
2004-05-01
期刊：
影响因子：
2.8
通讯作者：
Robson, CN
中科院分区：
文献类型：
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作者：
Halkidou, K;Gaughan, L;Robson, CN
背景组蛋白去乙酰化酶1（HDAC 1）是参与分化和增殖控制的共阻遏物。与良性组织相比，它在恶性组织中上调，并靶向包括p53在内的许多转录因子。通过免疫组织化学，研究了人前列腺标本和CWR 22小鼠异种移植模型中HDAC 1蛋白的表达。流式细胞术和去卷积免疫荧光也进行了。HDAC 1在癌前病变和恶性病变中上调，在激素难治性（HR）癌症中表达增加最多。利用CWR 22异种移植模型，我们发现HDAC 1的雄激素依赖性调节HDAC 1过表达导致组成型表达HDAC 1的PC 3 M衍生克隆的增殖显著增加，并向未分化的细胞角蛋白（CK）谱转变。这项研究强调了HDAC 1在细胞增殖和前列腺癌（CaP）发展中的重要性，并提出了HDAC 1核募集的机制。HDAC 1可能是一个重要的治疗靶点，特别是在雄激素非依赖性的最致命阶段。(C)2004 Wiley-Liss，Inc.
BACKGROUND. Histone deacetylase 1 (HDAC1) is a co-repressor involved in differentiation and proliferation control. It is upregulated in malignant compared to benign tissue, and targets a number of transcription factors including p53.METHODS. By immunohistochemistry, HDAC1 protein expression was investigated in human Prostate specimens and the CWR22 mouse xenograft model. Flow cytometry and deconvolution immunofluorescence were also performed.RESULTS. HDAC1 was upregulated in pre-malignant and malignant lesions, with the highest increase in expression in hormone refractory (HR) cancer. Using the CWR22 xenograft model we showed androgen dependent regulation of HDAC1 HDAC1 overexpression led to a significant increase in proliferation and a shift towards the undifferentiated cytokeratin (CK) profile in a PC3M derivative clone constitutively expressing HDAC1.CONCLUSION. This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence. (C) 2004 Wiley-Liss, Inc.