Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer.
Human DAB2IP (hDAB2IP), a novel GTPase-activating protein modulating the Ras-mediated signaling and tumor necrosis factor-mediated apoptosis, is a potent growth inhibitor in human prostate cancer (PCa). Loss of hDAB2IP expression in PCa is due to altered epigenetic regulation (i.e. DNA methylation and histone modification) of its promoter region. The elevated polycomb Ezh2, a histone methyltransferase, has been associated with PCa progression. In this study, we have demonstrated that an increased Ezh2 expression in normal prostatic epithelial cells can suppress hDAB2IP gene expression. In contrast, knocking down the endogenous Ezh2 levels in PCa by a specific small interfering RNA can increase hDAB2IP expression. The association of Ezh2 complex (including Eed and Suz12) with hDAB2IP gene promoter is also detected in PCa cells but not in normal prostatic epithelial cells. Increased Ezh2 expression in normal prostatic epithelial cells by cDNA transfection facilitates the recruitment of other components of Ezh2 complex to the hDAB2IP promoter region accompanied with the increased levels of methyl histone H3 (H3) and histone deacetylase (HDAC1). Consistently, data from PCa cells transfected with Ezh2 small interfering RNA demonstrated that reduced Ezh2 levels resulted in the dissociation of Ezh2 complex accompanied with decreased levels of both methyl H3 and HDAC1 from hDAB2IP gene promoter. We further unveiled that the methylation status of Lys-27 but not Lys-9 of H3 in hDAB2IP promoter region is consistent with the hDAB2IP levels in both normal prostatic epithelial cells and PCa cells. Together, we conclude that hDAB2IP gene is a target gene of Ezh2 in prostatic epithelium, which provides an underlying mechanism of the down-regulation of hDAB2IP gene in PCa.
Chen
Hong
H
Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110, USA.
Tu
Szu-wei
SW
Hsieh
Jer-Tsong
JT
D017209:Apoptosis; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D018450:Disease Progression; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D009362:Neoplasm Metastasis; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011485:Protein Binding; D011496:Protein Methyltransferases; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis*
C462952:DAB2IP protein, human; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006657:Histones; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D020703:ras GTPase-Activating Proteins; D008156:Luciferases; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases