hADA2a and hADA3 are required for acetylation, transcriptional activity and proliferative effects of β-catenin

Abstract

β-catenin is the key transcriptional activator of the Wnt pathway important for development and tissue homeostasis of multicellular organisms. Its deregulation contributes to many human cancers. The β-catenin transcriptional activator complex continues to be defined, but already contains several proteins with chromatin remodeling activity. Here we show that two members of histone acetyltransferase complexes without enzymatic activity, hADA2a and hADA3, are required for full activity of β-catenin. hADA2a and hADA3 physically interact with β-catenin, and the interaction is mediated through Armadillo repeats 6 through 12 and the C-terminal transactivation domain of β-catenin. Both hADA2a and hADA3 reside with β-catenin at the enhancer for the Wnt target gene c-Myc. RNA interference-mediated reduction of hADA2a and hADA3 results in reduced β-catenin acetylation, reduced activity in reporter gene assays and reduced activation of endogenous β-catenin target genes. Overall, loss of hADA2a and hADA3 negatively impacts β-catenin-mediated proliferation. Our studies identify hADA2a and hADA3 as crucial cofactors of β-catenin that are likely involved in the assembly of transactivation-competent β-catenin complexes at Wnt target genes. ©2008 Landes Bioscience.