Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer.
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.


CONCLUSIONS
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.
Halkidou
Kalipso
K
School of Surgical and Reproductive Sciences, The Medical School, University of Newcastle upon Tyne, United Kingdom.
Gaughan
Luke
L
Cook
Susan
S
Leung
Hing Y
HY
Neal
David E
DE
Robson
Craig N
CN
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology; D016207:Cytokines / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000473:pathology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases