Abstract
Heparanase-1 (HPSE-1) is an endoglycosidase that cleaves heparan sulfate. The physiological functions of HPSE-1 include embryo development, hair growth, wound healing, tumor growth, angiogenesis, metastasis, and inflammation. HPSE-1 expression was found to increase temporarily in the rat ventral prostate (VP) after castration. The promoter region of the Hpse-1 gene has estrogen-responsive elements, suggesting that the gene is regulated by estrogens. In this study, we investigated the expression of HPSE-1 in the VP of 90-day-old rats after neonatal exposure to a high dose of 17β-estradiol. HPSE-1 was not found by immunohistochemistry in the epithelium of estrogenized animals. To determine whether inhibition of Hpse-1 expression in the epithelium was due to pre- or post-transcriptional regulation, epithelial cells were isolated by centrifugation in Percoll gradient and the presence of Hpse-1 mRNA was investigated by RT-PCR. Hpse-1 mRNA was not detected in the estrogenized animals. Considering that Hpse-1 transcription could be inhibited by DNA methylation, we used the methylation-sensitive restriction enzyme HpaII and PCR to show that a single CCGG site at position +185 was more frequently methylated in the epithelium of estrogenized than in control animals. Immunohistochemistry for 5-methylcytidine revealed that the epithelial cell nuclei in estrogenized animals were heavily methylated. These results suggest that Hpse-1 expression was blocked in the epithelial cells of the VP, by estrogen imprinting by a pre-transcriptional mechanism involving DNA methylation.
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Acknowledgments
The authors are grateful to FAPESP (Grant no. 09/16150-6) and CNPq for financial support. TMA and RRR were recipients of FAPESP fellowships. HFC dedicates this paper to the memory of his father Emanuel S Carvalho.
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Augusto, T.M., Rosa-Ribeiro, R. & Carvalho, H.F. Neonatal exposure to high doses of 17β-estradiol results in inhibition of heparanase-1 expression in the adult prostate. Histochem Cell Biol 136, 609–615 (2011). https://doi.org/10.1007/s00418-011-0860-9
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DOI: https://doi.org/10.1007/s00418-011-0860-9