Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B

Jihong Chen,Feras M Ghazawi,Wafae Bakkar,Qiao Li

doi:10.1186/1476-4598-5-71

Abstract

BackgroundIn eukaryotic cells, the genomic DNA is packed with histones to form the nucleosome and chromatin structure. Reversible acetylation of the histone tails plays an important role in the control of specific gene expression. Mounting evidence has established that histone deacetylase inhibitors selectively induce cellular differentiation, growth arrest and apoptosis in variety of cancer cells, making them a promising class of anticancer drugs. However, the molecular mechanisms of the anti-cancer effects of these inhibitors have yet to be understood.ResultsHere, we report that a key determinant for the susceptibility of cancer cells to histone deacetylase inhibitors is their ability to maintain cellular Akt activity in response to the treatment. Also known as protein kinase B, Akt is an essential pro-survival factor in cell proliferation and is often deregulated during tumorigenesis. We show that histone deacetylase inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2 expression, which leads to Akt deactivation and apoptotic cell death. In addition, valproic acid and butyrate induce apoptosis through the caspase-dependent pathway. The activity of caspase-9 is robustly activated upon valproic acid or butyrate treatment. Constitutively active Akt is able to block the caspase activation and rescues cells from butyrate-induced apoptotic cell death.ConclusionOur study demonstrates that although the primary target of histone deacetylase inhibitors is transcription, it is the capacity of cells to maintain cellular survival networks that determines their fate of survival.

Highlights

Introduction of constitutively activeAkt prevents butyrateinduced apoptosis To further determine the role of Akt in counteracting the apoptosis induced by histone deacetylases (HDAC) inhibitors, we employed an ovarian cancer cell line stably integrated with an expression plasmid for a constitutively active Akt and a control cell line stably integrated with an empty vector [38]
Valproic acid and butyrate repress Akt1 and Akt2 expression and induce apoptosis in HeLa cells HDAC inhibitor-induced growth arrest and apoptotic cell death have been observed in a variety of solid and hematological cancers, but the mechanisms of their action remain obscure [17]
To understand the mechanism of apoptotic cell death induced by HDAC inhibitors such as valproic acid and butyrate, we employed HeLa cells derived from a human cervical cancer [40]

Summary

Introduction

Introduction of constitutively activeAkt prevents butyrateinduced apoptosis To further determine the role of Akt in counteracting the apoptosis induced by HDAC inhibitors, we employed an ovarian cancer cell line stably integrated with an expression plasmid for a constitutively active Akt and a control cell line stably integrated with an empty vector [38]. Mounting evidence has established that histone deacetylase inhibitors selectively induce cellular differentiation, growth arrest and apoptosis in variety of cancer cells, making them a promising class of anticancer drugs. The amino-terminal tails of histones are rich in positively charged lysine residues which form tight contacts with the negatively charged DNA backbones, restricting the accessibility of DNA for the binding of transcription regulators [4,5] This restrictive milieu needs to be relieved to allow the regulation of chromatin structure and function, and for gene activation to occur, which often is achieved through acetylation of the histone tails by histone acetyltransferases [6,7,8,9]. A short chain fatty acid, naturally produced by bacterial fermentation in the colon, has been designated as the most potent fatty acid in arresting cell proliferation [12] Both compounds are classified as HDAC inhibitors [13,14]. The molecular mechanisms of the anticancer effects of the HDAC inhibitors have yet to be understood

Methods

Results

Conclusion