Role of Sirtuin Histone Deacetylase SIRT1 in Prostate Cancer

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, 22Rν1, 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.

[1]  Yasunori Fujita,et al.  Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. , 2008, Biochemical and biophysical research communications.

[2]  M. Gottesman,et al.  SIRT1 Contributes in Part to Cisplatin Resistance in Cancer Cells by Altering Mitochondrial Metabolism , 2008, Molecular Cancer Research.

[3]  Y. Akao,et al.  A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. , 2008, Biochemical and biophysical research communications.

[4]  C. Napoli,et al.  High glucose downregulates endothelial progenitor cell number via SIRT1. , 2008, Biochimica et biophysica acta.

[5]  W. Hahn,et al.  The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth , 2008, PloS one.

[6]  M. Salto‐Tellez,et al.  Function of the SIRT1 protein deacetylase in cancer. , 2007, Biotechnology journal.

[7]  J. Weber,et al.  Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. , 2007, The Biochemical journal.

[8]  P. Scardino,et al.  Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer. , 2007, Human pathology.

[9]  Xianglin Shi,et al.  Cytoplasm‐localized SIRT1 enhances apoptosis , 2007, Journal of cellular physiology.

[10]  L. Forman,et al.  Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. , 2007, Molecular endocrinology.

[11]  T. Nagy,et al.  SIRT1 is significantly elevated in mouse and human prostate cancer. , 2007, Cancer research.

[12]  Andre Fischer,et al.  SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis , 2007, The EMBO journal.

[13]  Lulu Chen,et al.  The expression of SIRT1 in nonalcoholic fatty liver disease induced by high‐fat diet in rats , 2007, Liver international : official journal of the International Association for the Study of the Liver.

[14]  David Sinclair,et al.  Sirtuins in mammals: insights into their biological function. , 2007, The Biochemical journal.

[15]  Manel Esteller,et al.  Cross‐Talk between Aging and Cancer , 2007, Annals of the New York Academy of Sciences.

[16]  D. Tripathi,et al.  Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53 , 2007, FEBS letters.

[17]  G. Park,et al.  SIRT1 promotes DNA repair activity and deacetylation of Ku70 , 2007, Experimental & Molecular Medicine.

[18]  S. Wang,et al.  SIRT1 interacts with p73 and suppresses p73‐dependent transcriptional activity , 2007, Journal of cellular physiology.

[19]  Y. Kubo,et al.  Strong expression of a longevity-related protein, SIRT1, in Bowen’s disease , 2007, Archives of Dermatological Research.

[20]  L. Guarente,et al.  Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. , 2006, Genes & development.

[21]  W. Ying.  NAD+ and NADH in cellular functions and cell death. , 2006, Frontiers in bioscience : a journal and virtual library.

[22]  N. Pattabiraman,et al.  Hormonal Control of Androgen Receptor Function through SIRT1 , 2006, Molecular and Cellular Biology.

[23]  Brian K. Kennedy,et al.  Sirtuins in Aging and Age-Related Disease , 2006, Cell.

[24]  J. Boeke,et al.  The biochemistry of sirtuins. , 2006, Annual review of biochemistry.

[25]  R. DePinho,et al.  Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. , 2006, Cancer research.

[26]  Kelly M. McGarvey,et al.  Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation , 2006, PLoS genetics.

[27]  C. Kamel,et al.  SirT1 fails to affect p53‐mediated biological functions , 2006, Aging cell.

[28]  Y. Ouchi,et al.  Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras–MAPK signaling in human cancer cells , 2006, Oncogene.

[29]  P. Distefano,et al.  Inhibition of SIRT1 Catalytic Activity Increases p53 Acetylation but Does Not Alter Cell Survival following DNA Damage , 2006, Molecular and Cellular Biology.

[30]  J. Milner,et al.  Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. , 2005, Cancer research.

[31]  A. Rebbaa,et al.  Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. , 2005, Cancer research.

[32]  E. Greer,et al.  FOXO transcription factors at the interface between longevity and tumor suppression , 2005, Oncogene.

[33]  Izumi Horikawa,et al.  Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. , 2005, Molecular biology of the cell.

[34]  A. Fukamizu,et al.  Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  C. Chen,et al.  SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. , 2005, International journal of molecular medicine.

[36]  B. Morris,et al.  A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer , 2005, Journal of hypertension.

[37]  Michael M. Murphy,et al.  Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. , 2005, Cell metabolism.

[38]  L. N. Valenti,et al.  Nuclear Trapping of the Forkhead Transcription Factor FoxO1 via Sirt-dependent Deacetylation Promotes Expression of Glucogenetic Genes* , 2005, Journal of Biological Chemistry.

[39]  W. Gu,et al.  SIRT1 Deacetylation and Repression of p300 Involves Lysine Residues 1020/1024 within the Cell Cycle Regulatory Domain 1* , 2005, Journal of Biological Chemistry.

[40]  S. Nicosia,et al.  Suppression of FOXO1 activity by FHL2 through SIRT1‐mediated deacetylation , 2005, The EMBO journal.

[41]  T. Ikejima,et al.  Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2 cell death. , 2005, Journal of pharmacological sciences.

[42]  R. Marmorstein.  Structure and chemistry of the Sir2 family of NAD+-dependent histone/protein deactylases. , 2004, Biochemical Society transactions.

[43]  L. Partridge,et al.  The interaction between FOXO and SIRT1: tipping the balance towards survival. , 2004, Trends in cell biology.

[44]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[45]  Hidde Ploegh,et al.  Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. , 2004, Molecular cell.

[46]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[47]  Jun-Ping Liu,et al.  Signaling on telomerase: a master switch in cell aging and immortalization , 2004, Biogerontology.

[48]  P. Wijchers,et al.  FoxO6, a Novel Member of the FoxO Class of Transcription Factors with Distinct Shuttling Dynamics* , 2003, Journal of Biological Chemistry.

[49]  F. Alt,et al.  Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  P. Coffer,et al.  Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. , 2001, Biochemical Society transactions.

[51]  Rakesh Nagarajan,et al.  FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression , 2002, The Journal of Biological Chemistry.

[52]  D. Sinclair,et al.  Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1* , 2002, The Journal of Biological Chemistry.

[53]  Geert J. P. L. Kops,et al.  The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-21 , 2002, The Journal of Immunology.

[54]  S. Minucci,et al.  Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence , 2002, The EMBO journal.

[55]  S. Schreiber,et al.  Identification of a Class of Small Molecule Inhibitors of the Sirtuin Family of NAD-dependent Deacetylases by Phenotypic Screening* , 2001, The Journal of Biological Chemistry.

[56]  Delin Chen,et al.  Negative Control of p53 by Sir2α Promotes Cell Survival under Stress , 2001, Cell.

[57]  J. Lammers,et al.  Forkhead Transcription Factor FKHR-L1 Modulates Cytokine-Dependent Transcriptional Regulation of p27KIP1 , 2000, Molecular and Cellular Biology.

[58]  M. Newton,et al.  p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells. , 1999, Cancer research.

[59]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[60]  W. Cavenee,et al.  Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. , 1998, Genomics.

[61]  Yalin H. Wei,et al.  Cloning and characterization of the t(X;II) breakpoint from a leukemic cell line identify a new member of the forkhead gene family , 1994, Genes, chromosomes & cancer.

[62]  B. Emanuel,et al.  Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma , 1993, Nature Genetics.

[63]  C. Reznikoff,et al.  Growth kinetics and differentiation in vitro of normal human uroepithelial cells on collagen gel substrates in defined medium , 1987, Journal of cellular physiology.