Upregulation and nuclear recruitment of HDACI in hormone refractory prostate cancer

被引:406
作者
Halkidou, K
Gaughan, L
Cook, S
Leung, HY
Neal, DE
Robson, CN [1 ]
机构
[1] Univ Newcastle Upon Tyne, Sch Med, Sch Surg & Reprod Sci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[2] Addenbrookes Hosp, Ctr Oncol, Cambridge, England
关键词
prostate; HDAC1; hormone refractory; deacetylation; androgen ablation; proliferation;
D O I
10.1002/pros.20022
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:177 / 189
页数:13
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