title: Epigenetic regulation of phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 gene expression in prostate cancer cells.
abstract: Aberrant up-regulation of P-Rex1 expression plays important roles in cancer progression and metastasis. The present study investigated the regulatory mechanism underlying P-Rex1 gene expression in prostate cancer cells. We showed that P-Rex1 expression was much higher in metastatic prostate cancer cells than in prostate epithelial cells and non-metastatic prostate cancer cells. Histone deacetylase (HDAC) inhibitors or silence of endogenous HDAC1 and HDAC2 markedly elevated P-Rex1 transcription in non-metastatic prostate cancer cells, whereas overexpression of recombinant HDAC1 in metastatic prostate cancer cells suppressed P-Rex1 expression. HDAC inhibitor trichostatin A (TSA) also significantly increased P-Rex1 promoter activity and caused acetylated histones to accumulate and associate with the P-Rex1 promoter. One Sp1 site, essential for basal promoter activity, was identified as critical for the TSA effect. TSA treatment did not alter the DNA-binding activity of Sp1 toward the P-Rex1 promoter; however, it facilitated the dissociation of the repressive HDAC1 and HDAC2 from the Sp1 binding region. Interestingly, HDAC1 association with Sp1 and with the P-Rex1 promoter were much weaker in metastatic prostate cancer PC-3 cells than in non-metastatic prostate cancer cells, and HDAC inhibitors only had very modest stimulatory effects on P-Rex1 promoter activity and P-Rex1 expression in PC-3 cells. Altogether, our studies demonstrate that HDACs could regulate P-Rex1 gene transcription by interaction with Sp1 and by region-specific changes in histone acetylation within the P-Rex1 promoter. Disassociation of HDACs from Sp1 on the P-Rex1 promoter may contribute to aberrant up-regulation of P-Rex1 in cancer.
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
authors.forename: Chuu-Yun A
authors.initials: CY
authors.lastname: Wong
authors.forename: Hada
authors.initials: H
authors.lastname: Wuriyanghan
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
authors.forename: Peter W
authors.initials: PW
authors.lastname: Abel
authors.forename: Yaping
authors.initials: Y
authors.lastname: Tu
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C453280:PREX1 protein, human; D016329:Sp1 Transcription Factor; C012589:trichostatin A; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2