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Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition?

ABSTRACT: Prostate cancer (PCa) is a major age-related malignancy, and according to estimates from the American Cancer Society, a man's chance of developing this cancer significantly increases with increasing age, from 1 in 10,149 by age 39 to 1 in 38 by age 59 to 1 in 7 by age 70. Therefore, it is important to identify the causal connection between mechanisms of aging and PCa. Employing in vitro and in vivo approaches, in this study, we tested the hypothesis that SIRT1, which belongs to the Sir2 (silent information regulator 2) family of sirtuin class III histone deacetylases, is overexpressed in PCa, and its inhibition will have antiproliferative effects in human PCa cells. Our data demonstrated that SIRT1 was significantly overexpressed in human PCa cells (DU145, LNCaP, 22Rnu1, and PC3) compared with normal prostate epithelial cells (PrEC) at protein, mRNA, and enzymatic activity levels. SIRT1 was also found to be overexpressed in human PCa tissues compared with adjacent normal prostate tissue. Interestingly, our data demonstrated that SIRT1 inhibition via nicotinamide and sirtinol (at the activity level) as well as via short hairpin RNA-mediated RNA interference (at the genetic level) resulted in a significant inhibition in the growth and viability of human PCa cells while having no effect on normal prostate epithelial cells. Further, we found that inhibition of SIRT1 caused an increase in FOXO1 acetylation and transcriptional activation in PCa cells. Our data suggested that SIRT1, via inhibiting FOXO1 activation, could contribute to the development of PCa. We suggest that SIRT1 could serve as a target toward developing novel strategies for PCa management.

SUBMITTER: Jung-Hynes B

PROVIDER: S-EPMC2635052 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition?

Jung-Hynes Brittney B Nihal Minakshi M Zhong Weixiong W Ahmad Nihal N

The Journal of biological chemistry 20081215 6

Prostate cancer (PCa) is a major age-related malignancy, and according to estimates from the American Cancer Society, a man's chance of developing this cancer significantly increases with increasing age, from 1 in 10,149 by age 39 to 1 in 38 by age 59 to 1 in 7 by age 70. Therefore, it is important to identify the causal connection between mechanisms of aging and PCa. Employing in vitro and in vivo approaches, in this study, we tested the hypothesis that SIRT1, which belongs to the Sir2 (silent ...[more]

PMID: 19075016

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Project description:Background and purposeSepsis is a systemic inflammatory response accompanied by excessive production of inflammatory cytokines and cardiovascular dysfunction. Importantly, macrophage-derived pro-inflammatory agents play a key role in cardiovascular impairment in sepsis. Here we have investigated the effects of trimetazidine (TMZ) on pro-inflammatory responses of macrophages in endotoxin-induced myocardial dysfunction.Experimental approachMice pretreated with TMZ were injected i.p. with LPS and cardiac function evaluated. Levels of macrophage infiltration, macrophage inflammatory response and cardiomyocyte apoptosis were measured using immunohistochemical staining, elisa, real-time RT-PCR, Western blot, TUNEL and flow cytometry assays.Key resultsPretreatment with TMZ prevented LPS-induced myocardial dysfunction and apoptosis. TMZ also lowered levels of pro-inflammatory cytokines in serum and cardiac tissue and myocardial macrophage infiltration. Bone marrow transplantation indicated that TMZ alleviated LPS-induced myocardial dysfunction via decreasing macrophage infiltration. TMZ reduced expression of pro-inflammatory cytokines in LPS-stimulated cardiac and peritoneal macrophages. Co-culture of TMZ-pretreated macrophages with cardiomyocytes and conditioned media from TMZ-pretreated macrophages both decreased LPS-induced cardiomyocyte apoptosis. The anti-apoptosis effects of TMZ resulted from decrease of pro-inflammatory cytokines, partly due to normalizing the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK)/Nrf2/haem oxygenase-1 and Sirt1/PPARα pathways in macrophages. Cytokine secretion was also regulated by ROS, which were attenuated by TMZ via activation of Sirt1, AMPK and PPARα.Conclusions and implicationsTMZ protected against LPS-induced myocardial dysfunction and apoptosis, accompanied by inhibition of macrophage pro-inflammatory responses. Our studies suggest that TMZ might represent a novel therapeutic agent to prevent and treat sepsis-induced myocardial dysfunction.

Project description:Histone variants seem to play a major role in gene expression regulation. In prostate cancer, H2A.Z and its acetylated form are implicated in oncogenes' upregulation. SIRT1, which may act either as tumor suppressor or oncogene, reduces H2A.Z levels in cardiomyocytes, via proteasome-mediated degradation, and this mechanism might be impaired in prostate cancer cells due to sirtuin 1 downregulation. Thus, we aimed to characterize the mechanisms underlying H2A.Z and SIRT1 deregulation in prostate carcinogenesis and how they interact. We found that H2AFZ and SIRT1 were up- and downregulated, respectively, at transcript level in primary prostate cancer and high-grade prostatic intraepithelial neoplasia compared to normal prostatic tissues. Induced SIRT1 overexpression in prostate cancer cell lines resulted in almost complete absence of H2A.Z. Inhibition of mTOR had a modest effect on H2A.Z levels, but proteasome inhibition prevented the marked reduction of H2A.Z due to sirtuin 1 overexpression. Prostate cancer cells exposed to epigenetic modifying drugs trichostatin A, alone or combined with 5-aza-2'-deoxycytidine, increased H2AFZ transcript, although with a concomitant decrease in protein levels. Conversely, SIRT1 transcript and protein levels increased after exposure. ChIP revealed an increase of activation marks within the TSS region for both genes. Remarkably, inhibition of sirtuin 1 with nicotinamide, increased H2A.Z levels, whereas activation of sirtuin 1 by resveratrol led to an abrupt decrease in H2A.Z. Finally, protein-ligation assay showed that exposure to epigenetic modifying drugs fostered the interaction between sirtuin 1 and H2A.Z. We concluded that sirtuin 1 and H2A.Z deregulation in prostate cancer are reciprocally related. Epigenetic mechanisms, mostly histone post-translational modifications, are likely involved and impair sirtuin 1-mediated downregulation of H2A.Z via proteasome-mediated degradation. Epigenetic modifying drugs in conjunction with enzymatic modulators are able to restore the normal functions of sirtuin 1 and might constitute relevant tools for targeted therapy of prostate cancer patients.

Dataset Information

Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition?

Publications

Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition?

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