This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsubaki, J. Articles by Rosenfeld, R. G. Search for Related Content PubMed PubMed Citation Articles by Tsubaki, J. Articles by Rosenfeld, R. G.

Differential Activation of the IGF Binding Protein-3 Promoter by Butyrate in Prostate Cancer Cells

Department of Pediatrics (J.T., V.H., R.G.R.), Oregon Health Sciences University, Portland, Oregon 97201; and Kolling Institute of Medical Research (S.M.T.), University of Sydney, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Vivian Hwa, Department of Pediatrics, School of Medicine NRC5, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3402.

Sodium butyrate (NaB), a dietary micronutrient, is a potent growth inhibitor that initiates cell differentiation in many cell types, including prostate cancer cells. The molecular mechanisms by which these effects occur remain largely unknown. In this study, we investigated the effects of NaB on the expression of IGF binding protein (IGFBP)-3, a known growth regulator, in two human prostate cancer cell lines (PC-3 and LNCaP).

Treatment with NaB (0–10 mM) caused a dose-dependent stimulation of IGFBP-3 mRNA expression and parallel increases in protein levels. A specific histone deacetylase inhibitor, trichostatin A (TSA) similarly induced IGFBP-3 expression, indicating that histone hyperacetylation may be critical in the regulation of IGFBP-3 expression.

To investigate the molecular mechanism of NaB-regulated IGFBP-3 expression, 1.87 kb of the human IGFBP-3 gene promoter was cloned into the pGL2-basic luciferase reporter vector. In both PC-3 and LNCaP cells, NaB (10 mM) significantly increased luciferase activity 20- to 30-fold, compared with the untreated control. However, using 5' sequential deletion constructs of the IGFBP-3 promoter, the NaB response sequences in the IGFBP-3 promoter were different in PC-3 and LNCaP cells. Our studies identified a region, -75 to +69 from the start of transcription (+1), that is fully inducible by NaB treatment in LNCaP cells, but not in PC-3 cells. Unlike other well characterized NaB-regulated genes, Sp1 DNA sequences are not involved in NaB up-regulation of IGFBP-3 gene in LNCaP cells. Further deletion studies identified two independent regions critical for NaB-induced transactivation in LNCaP cells. These regions contain consensus binding sites for p53 and GATA, respectively, but mutational analyses and gel shift assays suggested that, while the p53 response element is required for NaB responsiveness, neither p53 nor GATA are involved.

In summary, we have demonstrated that 1) NaB significantly up-regulates IGFBP-3 mRNA and protein levels in PC-3 and LNCaP prostate cancer cells; and 2) novel butyrate- responsive elements lacking consensus Sp1 sites are used in LNCaP cells.

This article has been cited by other articles:

				V. Hwa, G. Haeusler, K. L. Pratt, B. M. Little, H. Frisch, D. Koller, and R. G. Rosenfeld Total Absence of Functional Acid Labile Subunit, Resulting in Severe Insulin-Like Growth Factor Deficiency and Moderate Growth Failure J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1826 - 1831. [Abstract] [Full Text] [PDF]

				M. Takaoka, C. E. Smith, M. K. Mashiba, T. Okawa, C. D. Andl, W. S. El-Deiry, and H. Nakagawa EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G404 - G416. [Abstract] [Full Text] [PDF]

				E. M. Ongeri, M. F. Verderame, and J. M. Hammond Follicle-Stimulating Hormone Induction of Ovarian Insulin-Like Growth Factor-Binding Protein-3 Transcription Requires a TATA Box-Binding Protein and the Protein Kinase A and Phosphatidylinositol-3 Kinase Pathways Mol. Endocrinol., July 1, 2005; 19(7): 1837 - 1848. [Abstract] [Full Text] [PDF]

				K. E. B. Knudsen, A. Serena, A. K. B. Kjaer, H. Jorgensen, and R. Engberg Rye Bread Enhances the Production and Plasma Concentration of Butyrate but Not the Plasma Concentrations of Glucose and Insulin in Pigs J. Nutr., July 1, 2005; 135(7): 1696 - 1704. [Abstract] [Full Text] [PDF]

				G. P. Dunn, K. C.F. Sheehan, L. J. Old, and R. D. Schreiber IFN Unresponsiveness in LNCaP Cells Due to the Lack of JAK1 Gene Expression Cancer Res., April 15, 2005; 65(8): 3447 - 3453. [Abstract] [Full Text] [PDF]

				J. Ye, D. Shedd, and G. Miller An Sp1 Response Element in the Kaposi's Sarcoma-Associated Herpesvirus Open Reading Frame 50 Promoter Mediates Lytic Cycle Induction by Butyrate J. Virol., February 1, 2005; 79(3): 1397 - 1408. [Abstract] [Full Text] [PDF]

				L.-C. Li, P. R. Carroll, and R. Dahiya Epigenetic Changes in Prostate Cancer: Implication for Diagnosis and Treatment J Natl Cancer Inst, January 19, 2005; 97(2): 103 - 115. [Abstract] [Full Text] [PDF]

				J. L. Merchant, L. Bai, and M. Okada ZBP-89 Mediates Butyrate Regulation of Gene Expression J. Nutr., July 1, 2003; 133(7): 2456S - 2460. [Abstract] [Full Text] [PDF]

				I. B. Roninson Tumor Cell Senescence in Cancer Treatment Cancer Res., June 1, 2003; 63(11): 2705 - 2715. [Abstract] [Full Text] [PDF]

				N. Camarero, A. Nadal, M. J. Barrero, D. Haro, and P. F. Marrero Histone deacetylase inhibitors stimulate mitochondrial HMG-CoA synthase gene expression via a promoter proximal Sp1 site Nucleic Acids Res., March 15, 2003; 31(6): 1693 - 1703. [Abstract] [Full Text] [PDF]