EZH2　plays　a　major　role　in　HIV-1　latency,　however,　the　molecular　linkage　between　Tat-induced　HIV-1　transactivation　and　EZH2　activity　is　not　fully　understood.　It　was　shown　Tat　induced　HIV-1　transactivation　through　inhibiting　EZH2　activity.　Tat　decreased　the　levels　of　H3K27me3　and　EZH2　occupy　at　the　long　terminal　repeat　(LTR)　of　HIV-1.　We　further　showed　for　the　first　time　that　transfected　with　Tat　construct　resulted　in　an　increase　in　phosphorylated　EZH2　(p-EZH2),　mediated　by　active　Akt.　ROS/Akt-dependent　p-EZH2　was　correlated　with　Tat-induced　transactivation.　Our　study　reveals　that　novel　mechanisms　allow　Tat-induced　HIV-1　transactivation　by　ROS/Akt-dependent　downregulating　the　EZH2　epigenetic　silencing　machinery.　(C)　2015　Federation　of　European　Biochemical　Societies.　Published　by　Elsevier　B.V.　All　rights　reserved.