Epigenetic regulation of phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 gene expression in prostate cancer cells.
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.
Mesh Terms:
Animals, Base Sequence, Binding Sites, Cell Line, Tumor, Epigenesis, Genetic, Epithelial Cells, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Male, Neoplasm Metastasis, Promoter Regions, Genetic, Prostatic Neoplasms, Sp1 Transcription Factor, Substrate Specificity, Transcriptional Activation, Up-Regulation
Animals, Base Sequence, Binding Sites, Cell Line, Tumor, Epigenesis, Genetic, Epithelial Cells, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Male, Neoplasm Metastasis, Promoter Regions, Genetic, Prostatic Neoplasms, Sp1 Transcription Factor, Substrate Specificity, Transcriptional Activation, Up-Regulation
J. Biol. Chem.
Date: Jul. 22, 2011
PubMed ID: 21636851
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