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Horm Metab Res 2012; 44(07): 511-519
DOI: 10.1055/s-0032-1311566
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Global Methylation Analysis Identifies PITX2 as an Upstream Regulator of the Androgen Receptor and IGF-I Receptor Genes in Prostate Cancer

H. Schayek
1   Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
,
I. Bentov
1   Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
,
J. Jacob-Hirsch
2   Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel
,
C. Yeung
3   Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
,
C. Khanna
3   Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
,
L. J. Helman
3   Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
,
S. R. Plymate
4   Department of Medicine, Gerontology and Geriatric Medicine, University of Washington and Grecc Vapshcs, Seattle, WA, USA
,
H. Werner
1   Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
› Author Affiliations
Further Information

Publication History

received 17 January 2012

accepted 13 March 2012

Publication Date:
11 April 2012 (online)

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Abstract

The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes (“methylome”) in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2′-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i. e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease.

Key words

insulin-like growth factor-I (IGF-I) - IGF-I receptor - DNA methylation - epigenetic regulation - androgen receptor - prostate cancer
 

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