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Histone Acetylation Up‐regulates Phosphatidylinositol‐3,4,5‐triphosphate‐dependent Rac Exchange Factor 1 (P‐Rex1) Expression to Promote Prostate Cancer Metastasis
Author(s) -
Wong ChuuYun Anny,
Ha Da,
Xie Yan,
Wolff Dennis W.,
Abel Peter W.,
Tu Yaping
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.964.7
Subject(s) - chromatin immunoprecipitation , cancer research , acetylation , histone , transcription factor , microbiology and biotechnology , rex1 , biology , chemistry , promoter , gene expression , cellular differentiation , biochemistry , adult stem cell , gene
We have reported that P‐Rex1 up‐regulation promotes metastasis, the major cause of prostate cancer death (Oncogene, 28: 1853–1863). The objective of this study was to combine biochemical, molecular and cellular techniques to define mechanisms underlying P‐Rex1 up‐regulation. Quantitative real‐time PCR and Western blot analysis indicated that histonedeacetylase (HDAC) inhibitors but not DNA methylation inhibitors increased P‐Rex1 expression in non‐metastatic prostate cancer cells to levels similar to that in metastatic prostate cancer PC‐3 cells. HDAC inhibitors enhanced P‐Rex1 promoter activity and a transcription factor Sp1 binding site in this promoter is responsible for the effect of HDAC inhibitors. Chromatin immunoprecipitation assays demonstrated that Sp1 association with the P‐Rex1 promoter is essential for P‐Rex1 expression. HDAC inhibitors caused dissociation of HDAC from Sp1, leading to histone acetylation and P‐Rex1 up‐regulation. Interestingly, HDAC1 over‐expression in PC‐3 cells caused histone deacetylation and P‐Rex1 down‐regulation, which inhibited metastatic activity in Transwell chamber assays. Our results demonstrate that histone acetylation stimulates P‐Rex1 expression in a Sp1‐dependent manner and suggest that targeting HDAC and Sp1 may provide a novel strategy for suppressing prostate cancer metastasis. Supported by NIH 1R011CA125661 and Department of Defense.