Dhordain P, Lin R J, Quief S, Lantoine D, Kerckaert J P, Evans R M, Albagli O
U124 INSERM/IRCL, Place de Verdun, F-59045 Lille cedex, France and Howard Hughes Medical Institute and The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Nucleic Acids Res. 1998 Oct 15;26(20):4645-51. doi: 10.1093/nar/26.20.4645.
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 components referred to as corepressors. For instance, the bHLH-Zip transcriptional repressors MAD/MXI recruit HDACs together with the mSIN3 corepressors, whereas unliganded nuclear receptors contact another corepressor, 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 involvedin the pathogenesis of non-Hodgkin lymphomas. However, whether LAZ3 recruits the HDACs-containing repression complex is currently unknown. We report here that LAZ3 associates with corepressor mSIN3A both in vivo and in vitro , and found that a central 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 show that LAZ3 also interacts with an HDAC (HDAC-1) through its POZ domain in vitro while the immunoprecipitation of LAZ3 results in the coretention of an endogenous HDAC activity in vivo . Finally, inhibitors of HDACs 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 transcription requires HDACs activity. Our results identify HDACs as molecular targets of LAZ3 oncogene and further strengthen the connection between aberrant chromatin acetylation and human cancers.
近期研究表明，一些转录抑制因子通过直接相互作用，或者作为包含其他被称为共抑制因子的多亚基抑制复合物的成员，来招募组蛋白去乙酰化酶（HDACs）。例如，bHLH-Zip转录抑制因子MAD/MXI与mSIN3共抑制因子一起招募HDACs，而未结合配体的核受体则与另一种共抑制因子SMRT（或其相关物N-CoR）接触，SMRT又与mSIN3和HDACs结合形成抑制复合物。最近，我们报道SMRT还直接与LAZ3（BCL-6）相互作用，LAZ3是一种参与非霍奇金淋巴瘤发病机制的POZ/锌指转录抑制因子。然而，目前尚不清楚LAZ3是否招募含HDACs的抑制复合物。我们在此报道，LAZ3在体内和体外均与共抑制因子mSIN3A相互作用，并发现一个具有自主抑制活性的中央区域主要负责这种相互作用。相反，mSIN3A的N端一半对于结合LAZ3既是必要的也是充分的。此外，我们表明LAZ3在体外也通过其POZ结构域与一种HDAC（HDAC-1）相互作用，而LAZ3的免疫沉淀在体内导致内源性HDAC活性的共保留。最后，HDACs抑制剂显著降低LAZ3介导的抑制作用。综上所述，我们得出结论，LAZ3招募了一个包含SMRT、mSIN3A和一种HDAC的抑制复合物，并且其对转录的完全抑制潜力需要HDACs的活性。我们的结果将HDACs鉴定为LAZ3癌基因的分子靶点，并进一步加强了异常染色质乙酰化与人类癌症之间的联系。
