A viral gene that inactivates histone deacetylase 1 (HDAC1); the role of HDAC1 in cellular proliferation

The alterations of histone and non-histone proteins by acetylation is emerging as part of important cellular processes controlling many functions in cells and also in the process of carcinogenesis. The best-studied modification of core histones is the reversible acetylation of conserved lysine residues within the N-terminal tails. Two types of enzymes, the histone acetyltransferases (HATs) and the histone deacetylases (HDACs) control the acetylation of histones and other substrates. Histone deacetylase inhibitors (HDACi) have been shown to be potent inducers of differentiation, growth arrest and apoptotic cell death of transformed cells and are therefore being studied as potential antitumor agents. Viruses accomplish to control the cellular transcriptional machinery to modify the host environment to the virus' advantage. Indeed, they have adopted various mechanisms to take over the acetylation signaling pathway. Recently, specific viral proteins have been characterized to interact with HATs and HDACs, thereby disrupting normal acetylation pathways and affecting viral and cellular gene expression. We have been focusing on the adenoviral gene Gam1. We found that Gam1, a gene essential for viral replication, inactivates histone deacetylase 1 (HDAC1). Consistent with its ability to inhibit HDAC1, Gam1 activates transcription. Gam1 expression mimics the treatment of cells by histone deacetylase inhibitor trichostatin A (TSA) by inducing the expression of certain cellular genes normally repressed through the action of HDACs. In the attempt to determine how does Gam1 inactivate HDAC1, we are studying various ways to interfere with HDAC1, as well as looking at the role of HDAC1 in cellular proliferation by knocking down HDAC1 in a variety of tumor cell lines.