Epigenetic regulation of human bone morphogenetic protein 6 gene expression in prostate cancer.

Abstract

Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor-beta (TGF-beta) superfamily, are multifunctional molecules that regulate bone induction and organ development. Among BMPs, BMP-6 has been shown to be overexpressed in prostate cancer and is speculated to be associated with bone-forming skeletal metastasis. We investigated the regulatory mechanism of the BMP-6 gene expression in prostate cancer cell lines DU-145, LNCaP, PC-3, and PC-3M with regard to the methylation status of the CpG island in the 5' flanking region of the human BMP-6 gene. By sequence-specific analysis of methylated cytosines, we show here that the methylation status of the CpG loci around the Sp1 site of the BMP-6 promoter is related to its steady-state expression and an alternative splicing of messenger RNA (mRNA) in prostate cancer cell lines. Furthermore, a study of clinical cases of benign and malignant prostate lesion by in situ hybridization showed that BMP-6 expression was high at both primary and secondary sites in cases of advanced cancer with metastasis. Demethylation of the CpG loci around the Spl binding site was shown in cases with high BMP-6 expression by sequencing analysis of the methylated cytosine from paraffin-embedded materials. Our results suggested that during cancer progression, besides inactivation of tumor suppressor genes by hypermethylation, activation of certain genes like BMP-6 by selective demethylation was a common epigenetic event giving a variable character to the invading and metastasizing cancer cells.

• Authors: H Tamada, R Kitazawa, K Gohji, S Kitazawa
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 16 Issue 3 Pg. 487-96 (Mar 2001) ISSN: 0884-0431 [Print] United States
• PMID: 11277266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMP2 protein, human
• BMP6 protein, human
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Protein 6
• Bone Morphogenetic Proteins
• Hedgehog Proteins
• Proteins
• Trans-Activators
• Transforming Growth Factor beta
• Cytosine

Topics

• Aged
• Blotting, Northern
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Protein 6
• Bone Morphogenetic Proteins (genetics)
• Cytosine
• DNA Methylation
• Gene Expression Regulation, Neoplastic
• Hedgehog Proteins
• Humans
• In Situ Hybridization
• Male
• Middle Aged
• Promoter Regions, Genetic
• Prostatic Hyperplasia (genetics)
• Prostatic Neoplasms (genetics, pathology, secondary)
• Proteins (genetics)
• Trans-Activators
• Transforming Growth Factor beta
• Tumor Cells, Cultured