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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.

Pubmed ID: 21636851

Authors

  • Wong CY
  • Wuriyanghan H
  • Xie Y
  • Lin MF
  • Abel PW
  • Tu Y

Journal

The Journal of biological chemistry

Publication Data

July 22, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: CA125661
  • Agency: NCI NIH HHS, Id: CA88184

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