THE LAZ3(BCL-6) ONCOPROTEIN RECRUITS A SMRT MSIN3A HISTONE DEACETYLASE CONTAINING COMPLEX TO MEDIATE TRANSCRIPTIONAL REPRESSION/

Recent works demonstrated that some transcriptional repressors recruit histone deacetylases (HDACs) either through direct interaction, or as a member of a multisubunit repressing complex containing other compon ents referred to as corepressors, For instance, the bHLH-Zip transcrip tional repressors MAD/MXI recruit HDACs together with the mSIN3 corepr essors, whereas unliganded nuclear receptors contact another corepress or, SMRT (or its relative N-CoR), which, in turn, associates with both mSIN3 and HDACs to form the repressor complex. Recently, we reported that SMRT also directly associates with LAZ3 (BCL-6), a POZ/Zn finger transcriptional repressor involved in the pathogenesis of non-Hodgkin lymphomas, However, whether LAZ3 recruits the HDACs-containing repress ion complex is currently unknown. We report here that LAZ3 associates with corepressor mSIN3A both in vivo and in vitro, and found that a ce ntral region, which harbours autonomous repression activity, is mainly responsible for this interaction. Conversely, the N-terminal half of mSIN3A is both necessary and sufficient to bind LAZ3, Moreover, we sho w that LAZ3 also interacts with an HDAC (HDAC-1) through its POZ domai n in vitro while the immunoprecipitation of LAZ3 results in the corete ntion of an endogenous HDAC activity in vivo. Finally, inhibitors of H DACs significantly reduce the LAZ3-mediated repression. Taken together , we conclude that LAZ3 recruits a repressing complex containing SMRT, mSIN3A and a HDAC, and that its full repressing potential on transcri ption requires HDACs activity. Our results identify HDACs as molecular targets of LAZ3 oncogene and further strengthen the connection betwee n aberrant chromatin acetylation and human cancers.