|Reference : Screening of histone deacetylase (HDAC) expression profiles in prostate cancer tissues l...|
|Scientific congresses and symposiums : Unpublished conference|
|Human health sciences : Urology & nephrology|
Life sciences : Anatomy (cytology, histology, embryology...) & physiology
Human health sciences : Oncology
|Screening of histone deacetylase (HDAC) expression profiles in prostate cancer tissues leads to the identification of HDAC8 as a novel marker of smooth muscle differentiation|
|Waltregny, David [Université de Liège - ULg > Département des sciences cliniques > Urologie - GIGA-R : Labo de recherche sur les métastases >]|
|Glénisson, Wendy [>>>>]|
|Tran, Syv Li [>>>>]|
|Jackers, Pascale [>>>>]|
|North, Brian [>>>>]|
|Weidle, Ulrich [>>>>]|
|Verdin, Eric [>>>>]|
|Castronovo, Vincenzo [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire - GIGA-R : Labo de recherche sur les métastases >]|
|6th annual meeting of ‘Innovators in Urology’|
|6-8 juin 2003|
|‘Innovators in Urology’|
|[en] histone ; deacetylase ; prostate cancer ; smooth muscle|
|[en] Background: Histone deacetylation mediated by histone deacetylases (HDAC) plays a key role in the regulation of gene expression. Inhibition of HDAC activity is associated with profound alterations in cellular biology, such as cell growth arrest, apoptosis and differentiation. It has been hypothesized that altered HDAC expression and/or activity could play a role in cancer development and progression.
Objectives: To investigate this possibility, we undertook a study in which we screened HDAC expression profiles in human prostate cancer. In addition, we sought to determine the specific biological effects of selected HDACs.
Methods: A variety of techniques, including immunochemistry, Q-RT-PCR, and immunobloting, were used to examine the expression of several class I and class II HDACs in human prostate cancer cell lines and matched malignant and non-malignant prostate tissues. Analysis of the specific biological effects of selected HDACs was performed after knocking down their expression with the use of specific small interfering RNAs (siRNA) and/or after forcing their overexpression by transfection of the cDNAs of interest.
Results: Normal prostate epithelial and stromal cells displayed distinct HDAC expression profiles, suggesting specific functions for these enzymes in the prostate. Human prostate cancer cells did not exhibit significant alterations in the abundance of any of the HDAC enzymes analyzed. One of the HDACs tested, herein referred to as HDACX, was specifically expressed, in vivo, by cells showing smooth muscle phenotype, including vascular and prostate smooth muscle cells and myoepithelial cells. HDACX expression co-localized with the expression of the specific smooth muscle marker alpha smooth muscle actin (alpha-SMA) in all human tissues tested. Nucleo-cytoplasmic fractionation experiments showed that HDACX was mainly expressed in the cytosol of human smooth muscle cells (HSMC) obtained from umbilical cord veins. Transfection experiments leading to overexpression of HDACX in mouse fibroblasts indicated that the enzyme was detected both in the cytosol and in the nucleus. By immunocytochemistry, it was observed that HDACX pattern of expression was reminiscent of actin stress fibers, suggesting that this HDAC may be involved in the regulation of the smooth muscle cell cytoskeleton. Trichostatin A (TSA), a specific global HDAC inhibitor, as well as specific HDACX siRNAs, were able to completely prevent the TGFß1-induced differentiation of fibroblasts into myofibroblasts, as assessed by alpha-SMA abundance. Forced downregulation of HDACX by siRNAs in HSMC caused a dramatic reduction in their contraction capacity, as determined with the use of hydrated collagen lattices contraction assays.
Conclusions : HDACs diplay distinct expression profiles among normal prostate epithelial and stromal cells. The abundance of the HDACs analyzed in this study is not altered in prostate cancer. Further experiments are required to determine whether the activity of these enzymes is altered in prostate cancer. We have identified for the first time an HDAC that (i) is specifically expressed in cells showing smooth muscle phenotype, (ii) is required for myofibroblastic differentiation, and (iii) is involved in smooth muscle cell contraction. This HDAC may become a target for the therapy of several pathological conditions, including chronic inflammation and cancer, in which myofibroblasts play a major role.
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