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BMC Cancer
Published in: BMC Cancer 1/2006

Open Access 01-12-2006 | Research article

Down regulation of PSA by C/EBPα is associated with loss of AR expression and inhibition of PSA promoter activity in the LNCaP cell Line

Authors: Hong Yin, Hanna S Radomska, Daniel G Tenen, Jonathan Glass

Published in: BMC Cancer | Issue 1/2006

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Abstract

Background

C/EBPα is a transcription factor essential for terminal differentiation of several cell types. It has not known if C/EBPα protein is expressed and functions in the prostate gland.

Methods

The presence of C/EBPα in normal and cancerous prostate epithelium was examined by immunochemistry. Over expression of C/EBPα in LNCaP cells was conducted with retrovirus-mediated transduction. PSA expression was examined by RT-PCR and western blot and PSA promoter activity by luciferase reporter assay.

Results

In normal prostate C/EBPα was expressed in the basal layer of the epithelium. In prostate cancer C/EBPα was detected at low levels throughout the cancers and in advanced prostate cancer C/EBPα expression was associated with decreased expression of AR and PSA. Overexpression of C/EBPα inhibited epigenetically PSA expression and was accompanied by the loss of expression of AR. Transient increase of C/EBPα inhibited the PSA promoter/enhancer activity independently of expression of AR.

Conclusion

In LNCaP cells C/EBPα over expression inhibits expression of PSA by AR -dependent and independent mechanisms and by extinguishing AR expression provides a model for hormonal independent cell growth.
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Literature
1.
Lekstrom-Himes J, Xanthopoulos KG: Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem. 1998, 273 (44): 28545-28548. 10.1074/jbc.273.44.28545.CrossRefPubMed
2.
Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W, Tenen DG: Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001, 27 (3): 263-270. 10.1038/85820.CrossRefPubMed
3.
Lin FT, Lane MD: CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci U S A. 1994, 91 (19): 8757-8761. 10.1073/pnas.91.19.8757.CrossRefPubMedPubMedCentral
4.
Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG: Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A. 1997, 94 (2): 569-574. 10.1073/pnas.94.2.569.CrossRefPubMedPubMedCentral
5.
Zhang P, Iwama A, Datta MW, Darlington GJ, Link DC, Tenen DG: Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis. J Exp Med. 1998, 188 (6): 1173-1184. 10.1084/jem.188.6.1173.CrossRefPubMedPubMedCentral
6.
Cammenga J, Mulloy JC, Berguido FJ, MacGrogan D, Viale A, Nimer SD: Induction of C/EBPalpha activity alters gene expression and differentiation of human CD34+ cells. Blood. 2003, 101 (6): 2206-2214. 10.1182/blood-2002-05-1546.CrossRefPubMed
7.
Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR, Tenen DG: c-Myc is a critical target for c/EBPalpha in granulopoiesis. Mol Cell Biol. 2001, 21 (11): 3789-3806. 10.1128/MCB.21.11.3789-3806.2001.CrossRefPubMedPubMedCentral
8.
Porse BT, Pedersen TA, Xu X, Lindberg B, Wewer UM, Friis-Hansen L, Nerlov C: E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo. Cell. 2001, 107 (2): 247-258. 10.1016/S0092-8674(01)00516-5.CrossRefPubMed
9.
Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA: C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol Cell. 2001, 8 (4): 817-828. 10.1016/S1097-2765(01)00366-5.CrossRefPubMed
10.
Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG: AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001, 7 (4): 444-451. 10.1038/86515.CrossRefPubMed
11.
Antonson P, Xanthopoulos KG: Molecular cloning, sequence, and expression patterns of the human gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha). Biochem Biophys Res Commun. 1995, 215 (1): 106-113. 10.1006/bbrc.1995.2439.CrossRefPubMed
12.
Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP, Lander ES, Loda M, Kantoff PW, Golub TR, Sellers WR: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell. 2002, 1 (2): 203-209. 10.1016/S1535-6108(02)00030-2.CrossRefPubMed
13.
Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D, Koeffler HP: Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood. 2002, 99 (4): 1332-1340. 10.1182/blood.V99.4.1332.CrossRefPubMed
14.
Stuart RO, Wachsman W, Berry CC, Wang-Rodriguez J, Wasserman L, Klacansky I, Masys D, Arden K, Goodison S, McClelland M, Wang Y, Sawyers A, Kalcheva I, Tarin D, Mercola D: In silico dissection of cell-type-associated patterns of gene expression in prostate cancer. Proc Natl Acad Sci U S A. 2004, 101 (2): 615-620. 10.1073/pnas.2536479100.CrossRefPubMedPubMedCentral
15.
Balk SP, Ko YJ, Bubley GJ: Biology of prostate-specific antigen. J Clin Oncol. 2003, 21 (2): 383-391. 10.1200/JCO.2003.02.083.CrossRefPubMed
16.
Lang SH, Sharrard RM, Stark M, Villette JM, Maitland NJ: Prostate epithelial cell lines form spheroids with evidence of glandular differentiation in three-dimensional Matrigel cultures. Br J Cancer. 2001, 85 (4): 590-599. 10.1054/bjoc.2001.1967.CrossRefPubMedPubMedCentral
17.
Planz B, Tabatabaei S, Kirley SD, Aretz HT, Wang Q, Lin CW, McDougal WS, Marberger M: Studies on the differentiation pathway and growth characteristics of epithelial culture cells of the human prostate. Prostate Cancer Prostatic Dis. 2004, 7 (1): 73-83. 10.1038/sj.pcan.4500704.CrossRefPubMed
18.
Hernandez J, Thompson IM: Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker. Cancer. 2004, 101 (5): 894-904. 10.1002/cncr.20480.CrossRefPubMed
19.
Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CAJ: Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004, 350 (22): 2239-2246. 10.1056/NEJMoa031918.CrossRefPubMed
20.
Loberg RD, Fielhauer JR, Pienta BA, Dresden S, Christmas P, Kalikin LM, Olson KB, Pienta KJ: Prostate-specific antigen doubling time and survival in patients with advanced metastatic prostate cancer. Urology. 2003, 62 Suppl 1: 128-133. 10.1016/j.urology.2003.10.026.CrossRefPubMed
21.
Koistinen H, Paju A, Koistinen R, Finne P, Lovgren J, Wu P, Seppala M, Stenman UH: Prostate-specific antigen and other prostate-derived proteases cleave IGFBP-3, but prostate cancer is not associated with proteolytically cleaved circulating IGFBP-3. Prostate. 2002, 50 (2): 112-118. 10.1002/pros.10039.CrossRefPubMed
22.
Sutkowski DM, Goode RL, Baniel J, Teater C, Cohen P, McNulty AM, Hsiung HM, Becker GW, Neubauer BL: Growth regulation of prostatic stromal cells by prostate-specific antigen. J Natl Cancer Inst. 1999, 91 (19): 1663-1669. 10.1093/jnci/91.19.1663.CrossRefPubMed
23.
Cohen P, Peehl DM, Graves HC, Rosenfeld RG: Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol. 1994, 142 (3): 407-415.CrossRefPubMed
24.
Romanov VI, Whyard T, Adler HL, Waltzer WC, Zucker S: Prostate cancer cell adhesion to bone marrow endothelium: the role of prostate-specific antigen. Cancer Res. 2004, 64 (6): 2083-2089. 10.1158/0008-5472.CAN-03-3487.CrossRefPubMed
25.
Kim J, Coetzee GA: Prostate specific antigen gene regulation by androgen receptor. J Cell Biochem. 2004, 93 (2): 233-241. 10.1002/jcb.20228.CrossRefPubMed
26.
Cleutjens KB, van der Korput HA, Ehren-van Eekelen CC, Sikes RA, Fasciana C, Chung LW, Trapman J: A 6-kb promoter fragment mimics in transgenic mice the prostate-specific and androgen-regulated expression of the endogenous prostate-specific antigen gene in humans. Mol Endocrinol. 1997, 11 (9): 1256-1265. 10.1210/me.11.9.1256.CrossRefPubMed
27.
Hisatake JI, Ikezoe T, Carey M, Holden S, Tomoyasu S, Koeffler HP: Down-Regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer. Cancer Res. 2000, 60 (19): 5494-5498.PubMed
28.
Shenk JL, Fisher CJ, Chen SY, Zhou XF, Tillman K, Shemshedini L: p53 represses androgen-induced transactivation of prostate-specific antigen by disrupting hAR amino- to carboxyl-terminal interaction. J Biol Chem. 2001, 276 (42): 38472-38479. 10.1074/jbc.M103652200.CrossRefPubMed
29.
Yeung F, Li X, Ellett J, Trapman J, Kao C, Chung LW: Regions of prostate-specific antigen (PSA) promoter confer androgen-independent expression of PSA in prostate cancer cells. J Biol Chem. 2000, 275 (52): 40846-40855. 10.1074/jbc.M002755200.CrossRefPubMed
30.
Birkenmeier EH, Gwynn B, Howard S, Jerry J, Gordon JI, Landschulz WH, McKnight SL: Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 1989, 3 (8): 1146-1156.CrossRefPubMed
31.
Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG: CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998, 18 (7): 4301-4314.CrossRefPubMedPubMedCentral
32.
Slomiany BA, D'Arigo KL, Kelly MM, Kurtz DT: C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription. Mol Cell Biol. 2000, 20 (16): 5986-5997. 10.1128/MCB.20.16.5986-5997.2000.CrossRefPubMedPubMedCentral
33.
Chandrasekaran C, Gordon JI: Cell lineage-specific and differentiation-dependent patterns of CCAAT/enhancer binding protein alpha expression in the gut epithelium of normal and transgenic mice. Proc Natl Acad Sci U S A. 1993, 90 (19): 8871-8875. 10.1073/pnas.90.19.8871.CrossRefPubMedPubMedCentral
34.
Rask K, Thorn M, Ponten F, Kraaz W, Sundfeldt K, Hedin L, Enerback S: Increased expression of the transcription factors CCAAT-enhancer binding protein-beta (C/EBBeta) and C/EBzeta (CHOP) correlate with invasiveness of human colorectal cancer. Int J Cancer. 2000, 86 (3): 337-343. 10.1002/(SICI)1097-0215(20000501)86:3<337::AID-IJC6>3.0.CO;2-3.CrossRefPubMed
35.
Piontkewitz Y, Enerback S, Hedin L: Expression of CCAAT enhancer binding protein-alpha (C/EBP alpha) in the rat ovary: implications for follicular development and ovulation. Dev Biol. 1996, 179 (1): 288-296. 10.1006/dbio.1996.0258.CrossRefPubMed
36.
Halmos B, Huettner CS, Kocher O, Ferenczi K, Karp DD, Tenen DG: Down-regulation and antiproliferative role of C/EBPalpha in lung cancer. Cancer Res. 2002, 62 (2): 528-534.PubMed
37.
Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, Yang A, Montironi R, McKeon F, Loda M: p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol. 2000, 157 (6): 1769-1775.CrossRefPubMedPubMedCentral
38.
Kurita T, Medina RT, Mills AA, Cunha GR: Role of p63 and basal cells in the prostate. Development. 2004, 131 (20): 4955-4964. 10.1242/dev.01384.CrossRefPubMed
39.
Wang GL, Iakova P, Wilde M, Awad S, Timchenko NA: Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity. Genes Dev. 2004, 18 (8): 912-925. 10.1101/gad.1183304.CrossRefPubMedPubMedCentral
40.
Wang GL, Timchenko NA: Dephosphorylated C/EBPalpha accelerates cell proliferation through sequestering retinoblastoma protein. Mol Cell Biol. 2005, 25 (4): 1325-1338. 10.1128/MCB.25.4.1325-1338.2005.CrossRefPubMedPubMedCentral
41.
Kinoshita H, Shi Y, Sandefur C, Meisner LF, Chang C, Choon A, Reznikoff CR, Bova GS, Friedl A, Jarrard DF: Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer. Cancer Res. 2000, 60 (13): 3623-3630.PubMed
42.
Sigala S, Tognazzi N, Rizzetti MC, Faraoni I, Missale C, Bonmassar E, Spano P: Nerve growth factor induces the re-expression of functional androgen receptors and p75(NGFR) in the androgen-insensitive prostate cancer cell line DU145. Eur J Endocrinol. 2002, 147 (3): 407-415. 10.1530/eje.0.1470407.CrossRefPubMed
43.
Plymate SR, Tennant MK, Culp SH, Woodke L, Marcelli M, Colman I, Nelson PS, Carroll JM, Roberts CTJ, Ware JL: Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors. Prostate. 2004, 61 (3): 276-290. 10.1002/pros.20099.CrossRefPubMed
44.
Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, Macvicar GR, Varambally S, Harwood J, Bismar TA, Kim R, Rubin MA, Pienta KJ: Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004, 64 (24): 9209-9216. 10.1158/0008-5472.CAN-04-2442.CrossRefPubMed
45.
Nakayama T, Watanabe M, Suzuki H, Toyota M, Sekita N, Hirokawa Y, Mizokami A, Ito H, Yatani R, Shiraishi T: Epigenetic regulation of androgen receptor gene expression in human prostate cancers. Lab Invest. 2000, 80 (12): 1789-1796.CrossRefPubMed
46.
Chattopadhyay S, Gong EY, Hwang M, Park E, Lee HJ, Hong CY, Choi HS, Cheong JH, Kwon HB, Lee K: The CCAAT enhancer-binding protein-alpha negatively regulates the transactivation of androgen receptor in prostate cancer cells. Mol Endocrinol. 2006, 20 (5): 984-995. 10.1210/me.2005-0240.CrossRefPubMed
Metadata
Title
Down regulation of PSA by C/EBPα is associated with loss of AR expression and inhibition of PSA promoter activity in the LNCaP cell Line
Authors
Hong Yin
Hanna S Radomska
Daniel G Tenen
Jonathan Glass
Publication date
01-12-2006
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2006
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-6-158

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