Epigenetic regulation of phosphatidylinositol 3,4,5-triphosphate-dependent rac exchanger 1 gene expression in prostate cancer cells

Chuu Yun A Wong, Hada Wuriyanghan, Yan Xie, Ming-Fong Lin, Peter W. Abel, Yaping Tu

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)25813-25822
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number29
DOIs
StatePublished - Jul 22 2011

Fingerprint

Epigenomics
Gene expression
Prostatic Neoplasms
trichostatin A
Cells
Gene Expression
Histone Deacetylase Inhibitors
Transcription
Histones
Acetylation
Up-Regulation
phosphatidylinositol 3,4,5-triphosphate
Genes
Association reactions
Prostate
Neoplasms
Epithelial Cells
DNA
Neoplasm Metastasis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Epigenetic regulation of phosphatidylinositol 3,4,5-triphosphate-dependent rac exchanger 1 gene expression in prostate cancer cells. / Wong, Chuu Yun A; Wuriyanghan, Hada; Xie, Yan; Lin, Ming-Fong; Abel, Peter W.; Tu, Yaping.

In: Journal of Biological Chemistry, Vol. 286, No. 29, 22.07.2011, p. 25813-25822.

Research output: Contribution to journalArticle

Wong, Chuu Yun A ; Wuriyanghan, Hada ; Xie, Yan ; Lin, Ming-Fong ; Abel, Peter W. ; Tu, Yaping. / Epigenetic regulation of phosphatidylinositol 3,4,5-triphosphate-dependent rac exchanger 1 gene expression in prostate cancer cells. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 29. pp. 25813-25822.
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