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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

01-12-2020 | Prostate Cancer | Research

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

Authors: Irene Cosi, Annamaria Pellecchia, Emanuele De Lorenzo, Eugenio Torre, Michela Sica, Gabriella Nesi, Rosario Notaro, Maria De Angioletti

Published in: Journal of Hematology & Oncology | Issue 1/2020

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Abstract

Background

ETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model.

Methods

We have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays.

Results

ETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice.

Conclusions

ETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.
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Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.PubMed
2.
3.
Paulo P, Barros-Silva JD, Ribeiro FR, Ramalho-Carvalho J, Jeronimo C, Henrique R, et al. FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer. Genes Chromosomes Cancer. 2012;51(3):240–9.
4.
Arora K, Barbieri CE. Molecular subtypes of prostate cancer. Curr Oncol Rep. 2018;20(8):58.PubMed
5.
Nicholas TR, Strittmatter BG, Hollenhorst PC. Oncogenic ETS factors in prostate cancer. Adv Exp Med Biol. 2019;1210:409–36.PubMed
6.
Yu C, Hu K, Nguyen D, Wang ZA. From genomics to functions: preclinical mouse models for understanding oncogenic pathways in prostate cancer. Am J Cancer Res. 2019;9(10):2079–102.PubMedPubMedCentral
7.
Arriaga JM, Abate-Shen C. Genetically engineered mouse models of prostate cancer in the postgenomic era. Cold Spring Harb Perspect Med. 2019;9(2):a030528.PubMed
8.
Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448(7153):595–9.PubMed
9.
Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci U S A. 2008;105(6):2105–10.PubMedPubMedCentral
10.
Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia. 2008;10(2):177–88.PubMedPubMedCentral
11.
Zong Y, Xin L, Goldstein AS, Lawson DA, Teitell MA, Witte ON. ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc Natl Acad Sci U S A. 2009;106(30):12465–70.PubMedPubMedCentral
12.
Shin S, Kim TD, Jin F, van Deursen JM, Dehm SM, Tindall DJ, et al. Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. Cancer Res. 2009;69(20):8102–10.PubMedPubMedCentral
13.
Carver BS, Tran J, Chen Z, Carracedo-Perez A, Alimonti A, Nardella C, et al. ETS rearrangements and prostate cancer initiation. Nature. 2009;457(7231):E1 discussion E2-3.PubMedPubMedCentral
14.
Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 2009;41(5):619–24.PubMedPubMedCentral
15.
King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet. 2009;41(5):524–6.PubMedPubMedCentral
16.
Casey OM, Fang L, Hynes PG, Abou-Kheir WG, Martin PL, Tillman HS, et al. TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. PLoS One. 2012;7(7):e41668.PubMedPubMedCentral
17.
Baena E, Shao Z, Linn DE, Glass K, Hamblen MJ, Fujiwara Y, et al. ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes Dev. 2013;27(6):683–98.PubMedPubMedCentral
18.
Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med. 2013;19(8):1023–9.PubMedPubMedCentral
19.
Hida K, Shindoh M, Yoshida K, Kudoh A, Furaoka K, Kohgo T, et al. Expression of E1AF, an ets-family transcription factor, is correlated with the invasive phenotype of oral squamous cell carcinoma. Oral Oncol. 1997;33(6):426–30.PubMed
20.
Benz CC, O'Hagan RC, Richter B, Scott GK, Chang CH, Xiong X, et al. HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer. Oncogene. 1997;15(13):1513–25.PubMed
21.
de Launoit Y, Chotteau-Lelievre A, Beaudoin C, Coutte L, Netzer S, Brenner C, et al. The PEA3 group of ETS-related transcription factors. Role in breast cancer metastasis. Adv Exp Med Biol. 2000;480:107–16.PubMed
22.
Hiroumi H, Dosaka-Akita H, Yoshida K, Shindoh M, Ohbuchi T, Fujinaga K, et al. Expression of E1AF/PEA3, an Ets-related transcription factor in human non-small-cell lung cancers: its relevance in cell motility and invasion. Int J Cancer. 2001;93(6):786–91.PubMed
23.
Moss AC, Lawlor G, Murray D, Tighe D, Madden SF, Mulligan AM, et al. ETV4 and Myeov knockdown impairs colon cancer cell line proliferation and invasion. Biochem Biophys Res Commun. 2006;345(1):216–21.PubMed
24.
Upadhyay S, Liu C, Chatterjee A, Hoque MO, Kim MS, Engles J, et al. LKB1/STK11 suppresses cyclooxygenase-2 induction and cellular invasion through PEA3 in lung cancer. Cancer Res. 2006;66(16):7870–9.PubMed
25.
Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 2006;66(7):3396–400.PubMed
26.
Han B, Mehra R, Dhanasekaran SM, Yu J, Menon A, Lonigro RJ, et al. A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer. Cancer Res. 2008;68(18):7629–37.PubMedPubMedCentral
27.
Hermans KG, Bressers AA, van der Korput HA, Dits NF, Jenster G, Trapman J. Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer. Cancer Res. 2008;68(9):3094–8.PubMed
28.
Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI, et al. TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res. 2006;66(21):10242–6.PubMed
29.
Dedigama-Arachchige P, Carskadon S, Li J, Loveless I, Alhamar M, Peabody JO, et al. Clonal evaluation of prostate cancer molecular heterogeneity in biopsy samples by dual immunohistochemistry and dual RNA in situ hybridization. Mod Pathol. 2020. Online ahead of print.
30.
Higashino F, Yoshida K, Noumi T, Seiki M, Fujinaga K. Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters. Oncogene. 1995;10(7):1461–3.PubMed
31.
Horiuchi S, Yamamoto H, Min Y, Adachi Y, Itoh F, Imai K. Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer. J Pathol. 2003;200(5):568–76.PubMed
32.
Shindoh M, Higashino F, Kohgo T. E1AF, an ets-oncogene family transcription factor. Cancer Lett. 2004;216(1):1–8.PubMed
33.
Hollenhorst PC, Paul L, Ferris MW, Graves BJ. The ETS gene ETV4 is required for anchorage-independent growth and a cell proliferation gene expression program in PC3 prostate cells. Genes Cancer. 2011;1(10):1044–52.PubMed
34.
Pellecchia A, Pescucci C, De Lorenzo E, Luceri C, Passaro N, Sica M, et al. Overexpression of ETV4 is oncogenic in prostate cells through promotion of both cell proliferation and epithelial to mesenchymal transition. Oncogenesis. 2012;1:e20.PubMedPubMedCentral
35.
Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene. 1995;11(2):211–9.PubMed
36.
Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8(4):253–67.PubMed
37.
Cheville JC, Lloyd RV, Sebo TJ, Cheng L, Erickson L, Bostwick DG, et al. Expression of p27kip1 in prostatic adenocarcinoma. Mod Pathol. 1998;11(4):324–8.PubMed
38.
Drobnjak M, Melamed J, Taneja S, Melzer K, Wieczorek R, Levinson B, et al. Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Clin Cancer Res. 2003;9(7):2613–9.PubMed
39.
Noda H, Maehara Y, Irie K, Kakeji Y, Yonemura T, Sugimachi K. Growth pattern and expressions of cell cycle regulator proteins p53 and p21WAF1/CIP1 in early gastric carcinoma. Cancer. 2001;92(7):1828–35.PubMed
40.
Shoji T, Tanaka F, Takata T, Yanagihara K, Otake Y, Hanaoka N, et al. Clinical significance of p21 expression in non-small-cell lung cancer. J Clin Oncol. 2002;20(18):3865–71.PubMed
41.
Shariat SF, Tokunaga H, Zhou J, Kim J, Ayala GE, Benedict WF, et al. p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol. 2004;22(6):1014–24.PubMed
42.
Jiang J, Wei Y, Liu D, Zhou J, Shen J, Chen X, et al. E1AF promotes breast cancer cell cycle progression via upregulation of Cyclin D3 transcription. Biochem Biophys Res Commun. 2007;358(1):53–8.PubMed
43.
Somlo G, Chu P, Frankel P, Ye W, Groshen S, Doroshow JH, et al. Molecular profiling including epidermal growth factor receptor and p21 expression in high-risk breast cancer patients as indicators of outcome. Ann Oncol. 2008;19(11):1853–9.PubMedPubMedCentral
44.
Matsushima H, Sasaki T, Goto T, Hosaka Y, Homma Y, Kitamura T, et al. Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance. Hum Pathol. 1998;29(8):778–83.PubMed
45.
Cheng L, Lloyd RV, Weaver AL, Pisansky TM, Cheville JC, Ramnani DM, et al. The cell cycle inhibitors p21WAF1 and p27KIP1 are associated with survival in patients treated by salvage prostatectomy after radiation therapy. Clin Cancer Res. 2000;6(5):1896–9.PubMed
46.
Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 2000;275(32):24500–5.PubMed
47.
Murillo H, Huang H, Schmidt LJ, Smith DI, Tindall DJ. Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology. 2001;142(11):4795–805.PubMed
48.
Lacombe L, Maillette A, Meyer F, Veilleux C, Moore L, Fradet Y. Expression of p21 predicts PSA failure in locally advanced prostate cancer treated by prostatectomy. Int J Cancer. 2001;95(3):135–9.PubMed
49.
Omar EA, Behlouli H, Chevalier S, Aprikian AG. Relationship of p21(WAF-I) protein expression with prognosis in advanced prostate cancer treated by androgen ablation. Prostate. 2001;49(3):191–9.PubMed
50.
Network TCGAR. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015;163(4):1011–25.
51.
Zhang J, Thomas TZ, Kasper S, Matusik RJ. A small composite probasin promoter confers high levels of prostate-specific gene expression through regulation by androgens and glucocorticoids in vitro and in vivo. Endocrinology. 2000;141(12):4698–710.PubMed
52.
Shappell SB, Thomas GV, Roberts RL, Herbert R, Ittmann MM, Rubin MA, et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 2004;64(6):2270–305.PubMed
53.
Ittmann M, Huang J, Radaelli E, Martin P, Signoretti S, Sullivan R, et al. Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res. 2013;73(9):2718–36.PubMedPubMedCentral
54.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5.PubMedPubMedCentral
55.
el-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, et al. Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res. 1995;55(13):2910–9.PubMed
56.
Wu X, Wu J, Huang J, Powell WC, Zhang J, Matusik RJ, et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev. 2001;101(1-2):61–9.PubMed
57.
Kaya M, Yoshida K, Higashino F, Mitaka T, Ishii S, Fujinaga K. A single ets-related transcription factor, E1AF, confers invasive phenotype on human cancer cells. Oncogene. 1996;12(2):221–7.PubMed
58.
Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14(2):159–69.PubMed
59.
Mesquita D, Barros-Silva JD, Santos J, Skotheim RI, Lothe RA, Paulo P, et al. Specific and redundant activities of ETV1 and ETV4 in prostate cancer aggressiveness revealed by co-overexpression cellular contexts. Oncotarget. 2015;6(7):5217–36.PubMedPubMedCentral
60.
Ratovitski EA. LKB1/PEA3/DeltaNp63 pathway regulates PTGS-2 (COX-2) transcription in lung cancer cells upon cigarette smoke exposure. Oxid Med Cell Longev. 2010;3(5):317–24.PubMedPubMedCentral
61.
Mounir Z, Lin F, Lin VG, Korn JM, Yu Y, Valdez R, et al. TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene. 2014;34(29):3815–25.PubMed
62.
Xing X, Wang SC, Xia W, Zou Y, Shao R, Kwong KY, et al. The ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis. Nat Med. 2000;6(2):189–95.PubMed
63.
Discenza MT, Vaz D, Hassell JA, Pelletier J. Activation of the WT1 tumor suppressor gene promoter by Pea3. FEBS Lett. 2004;560(1-3):183–91.PubMed
64.
Galang CK, Muller WJ, Foos G, Oshima RG, Hauser CA. Changes in the expression of many Ets family transcription factors and of potential target genes in normal mammary tissue and tumors. J Biol Chem. 2004;279(12):11281–92.PubMed
65.
Clementz AG, Rogowski A, Pandya K, Miele L, Osipo C. NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications. Breast Cancer Res. 2011;13(3):R63.PubMedPubMedCentral
66.
Yu Z, Xia W, Wang HY, Wang SC, Pan Y, Kwong KY, et al. Antitumor activity of an Ets protein, PEA3, in breast cancer cell lines MDA-MB-361DYT2 and BT474M1. Mol Carcinog. 2006;45(9):667–75.PubMed
67.
Benbow U, Schoenermark MP, Orndorff KA, Givan AL, Brinckerhoff CE. Human breast cancer cells activate procollagenase-1 and invade type I collagen: invasion is inhibited by all-trans retinoic acid. Clin Exp Metastasis. 1999;17(3):231–8.PubMed
68.
Funaoka K, Shindoh M, Yoshida K, Hanzawa M, Hida K, Nishikata S, et al. Activation of the p21(Waf1/Cip1) promoter by the ets oncogene family transcription factor E1AF. Biochem Biophys Res Commun. 1997;236(1):79–82.PubMed
69.
Oh S, Shin S, Janknecht R. ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors. Biochim Biophys Acta. 2012;1826(1):1–12.PubMedPubMedCentral
70.
Li R, Pei H, Watson DK. Regulation of Ets function by protein - protein interactions. Oncogene. 2000;19(55):6514–23.PubMed
71.
Aytes A, Mitrofanova A, Kinkade CW, Lefebvre C, Lei M, Phelan V, et al. ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. Proc Natl Acad Sci U S A. 2013;110(37):E3506–15.PubMedPubMedCentral
Metadata
Title
ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21
Authors
Irene Cosi
Annamaria Pellecchia
Emanuele De Lorenzo
Eugenio Torre
Michela Sica
Gabriella Nesi
Rosario Notaro
Maria De Angioletti
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00943-w

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