Abstract
The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors (Trichostatin A, SAHA and sodium butyrate) promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells) and cervix carcinoma cells (HeLa). We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1). Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer-associated morbidity and mortality among adults worldwide despite existing therapies [1].The onset and progression of this disease results from an accumulation of genetic and epigenetic defects that allow for altered gene expression and overabundance of tumor promoting factors [2].In normal intestinal epithelium, post-transcriptional mechanisms play a crucial role in regulating the expression of growth-promoting and inflammation-associated gene expression [3]
Our results show that histone deacetylase (HDAC) inhibitors induce TTP expression at the transcriptional level, leading to the downregulation of the AU-rich element (ARE)-containing gene, COX-2
In order to determine that induction of TTP in response to HDAC inhibitor treatment reflects an actual transcriptional event, we examined the ability of trichostatin A (TSA) to influence TTP promoter activity
Summary
Colorectal cancer (CRC) is a leading cause of cancer-associated morbidity and mortality among adults worldwide despite existing therapies (surgery, radiotherapy and chemotherapeutic agents) [1]. A conserved feature associated with these genes is the AU-rich element (ARE) present in the mRNA 3' untranslated region (3' UTR) This cis-acting regulatory element serves as sites for trans-acting RNA-binding proteins that mediate events leading to rapid mRNA decay or stability [4]. During the process of CRC development, the ability of the ARE to function as an mRNA decay element is lost allowing for overexpression of factors that promote tumor growth, invasion, and angiogenesis [5,6,7]. Further analysis indicated an indirect epigenetic regulation of TTP was occurring and TTP induction was owing to an upregulation of EGR1, a known transcription factor for TTP These findings bring new insights into loss of post-transcriptional regulatory circuits during CRC tumor development and demonstrate that HDAC inhibitors could restore TTP expression in cancer cells, providing clinical perspectives for these compounds
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