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      Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

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          Abstract

          High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study.

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          Cancer statistics, 2007.

          Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward … (2007)
          Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. This report considers incidence data through 2003 and mortality data through 2004. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007. Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 0.3% per year in women; and a 13.6% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
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            Epigenetic therapy of cancer: past, present and future.

            Christine Yoo, Peter A. Jones (2006)
            The initiation and progression of cancer is controlled by both genetic and epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.
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              Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer.

              Anna Velcich, John Mariadason, Chris C. Wilson … (2006)
              Inhibitors of histone deacetylases (HDACs) induce growth arrest, differentiation, and apoptosis of colon cancer cell lines in vitro and have demonstrated anti-cancer efficacy in clinical trials. Whereas a role for HDAC1 and -2 in mediating components of the HDAC inhibitor response has been reported, the role of HDAC3 is unknown. Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638(N/+) mice. HDAC3 was also maximally expressed in proliferating crypt cells in normal intestine. Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increased apoptosis. Similar effects were observed for HDAC2 and, to a lesser extent, for HDAC1. HDAC3 silencing also selectively induced expression of alkaline phosphatase, a marker of colon cell maturation. Concurrent with its effect on cell growth, overexpression of HDAC3 and other Class I HDACs inhibited basal and butyrate-induced p21 transcription in a Sp1/Sp3-dependent manner, whereas silencing of HDAC3 stimulated p21 promoter activity and expression. However, the magnitude of the effects elicited by silencing of individual Class I HDACs was significantly less than that induced by HDAC inhibitors. These findings identify HDAC3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression. These findings also demonstrate that multiple Class I HDACs are involved in repressing p21 and suggest that the growth-inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Electronic): 22 January 2008
                Publication date Collection: 05 February 2008
                Publication date (Print): 12 February 2008
                Volume: 98
                Issue: 3
                Pages: 604-610
                Affiliations
                [1 ]Institute of Pathology, Charité – Universitätsmedizin Berlin, Germany
                [2 ]Therapeutic Area Oncology, Nycomed GmbH Konstanz, Germany
                [3 ]Department of Urology, Charité – Universitätsmedizin Berlin, Germany
                [4 ]Institute of Surgical Pathology – University Hospital Zurich Zurich, Switzerland
                Author notes
                [* ]Author for correspondence: glen.kristiansen@ 123456usz.ch
                Article
                Publisher Item ID: 6604199
                DOI: 10.1038/sj.bjc.6604199
                PMC ID: 2243142
                PubMed ID: 18212746
                SO-VID: 21da5d9a-a882-4a32-b4c2-09f7bc3e3de9
                Copyright © Copyright 2008, Cancer Research UK
                History
                Date received : 16 October 2007
                Date revision received : 18 December 2007
                Date accepted : 19 December 2007
                Categories
                Subject: Molecular Diagnostics

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: prostate cancer,prognostic marker,hdac,immunohistochemistry
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: prostate cancer, prognostic marker, hdac, immunohistochemistry

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