Histone deacetylases inhibit PIP3‐dependent Rac exchange factor 1 (P‐Rex1) expression in prostate cancer cells via SP1 binding site

Abstract

Previously, we reported that up‐regulation of P‐Rex1, a PIP3 and Gâã ‐activated GEF for Rac, promotes prostate cancer metastasis. Highly‐metastatic prostate cancer PC3 cells display constitutive P‐Rex1 expression whereas the level of P‐Rex1 is almost undetectable in normal prostate epithelial cells and nonmetastatic prostate cancer CWR22 Rv1 cells. Here, we show that P‐Rex1 expression is strongly stimulated by the treatment of TSA, a histone deacetylase inhibitor, in CWR22 Rv1 cells, but not in PC3 cells. Expression level of HDAC1 and HDAC2 are lower in PC3 cells than in CWR22 Rv1 cells. Using CHIP assay, we found that class I histone deacetylase HDAC1 and HDAC2 are bound to the endogenous P‐Rex1 promoter in CWR22 Rv1 cells, but not in PC3 cells. TSA treatment results in the dissociation of HDAC1/HDAC2 and increases of acetylated histone H4 in the promoter region of the P‐Rex1 gene in CWR22 Rv1 cells, subsequently causing the upregulation of P‐Rex1 expression. A putative SP1(Specificity Protein 1) binding site is identified as a TSA‐response element in the P‐Rex1 promoter. Activity of the SP1 transcription factor is indispensable for both TSA‐induced and constitutive P‐Rex1 expression. Further investigation revealed that SP1 may recruit HDAC1 to the P‐Rex1 promoter. Altogether, our results illustrate a SP1‐mediated histone acetylation‐related regulatory mechanism of P‐Rex1 expression in prostate cancer cells.