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.
Highlights
The abbreviations used areP-Rex, phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1; Histone deacetylase (HDAC), histone deacetylase; TSA, trichostatin A; MMA, mithramycin A; pRL-tk, TK-Renilla plasmid; 5-Aza-dC, 5-aza-2Ј-deoxycytidine; NaB, sodium butyrate
Rac is a member of the Rho family of small G-proteins that are important regulators of the cell cytoskeleton during the establishment of cell polarity and cell processes such as migration, vesicle trafficking, and cell division [1, 2]
P-Rex1 expression is normally repressed in most cells, suggesting that epigenetic mechanisms may be responsible for its low levels, whereas a reversal of epigenetic inhibition could contribute to the elevated expression of P-Rex1 during the later phases of prostate cancer progression
Summary
P-Rex, phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1; HDAC, histone deacetylase; TSA, trichostatin A; MMA, mithramycin A; pRL-tk, TK-Renilla plasmid; 5-Aza-dC, 5-aza-2Ј-deoxycytidine; NaB, sodium butyrate. Histone Deacetylases Regulate P-Rex Expression via a Promoter Sp1 Site mechanisms may be involved in P-Rex up-regulation in metastatic prostate cancer cells. Recent evidence has suggested that DNA-change-independent or epigenetic events, such as aberrant histone modifications and DNA methylation, play an important role in transcriptional regulation of a number of target genes, critical for prostate tumor progression (19 –22). P-Rex expression is normally repressed in most cells, suggesting that epigenetic mechanisms may be responsible for its low levels, whereas a reversal of epigenetic inhibition could contribute to the elevated expression of P-Rex during the later phases of prostate cancer progression. We demonstrate for the first time that HDACs have a major role in suppressing Sp1-driven P-Rex gene transcription. Disassociation of HDACs from Sp1 on the P-Rex promoter may contribute to aberrant up-regulation of P-Rex in metastatic prostate cancer cells
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