Dardis Gabrielle J, Wang Jun, Simon Jeremy M, Wang Gang Greg, Baldwin Albert S
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
iScience. 2023 Jun 14;26(7):107115. doi: 10.1016/j.isci.2023.107115. eCollection 2023 Jul 21.
The histone methyltransferase EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting paradoxical gene expression through interactions with transcription factors, including NF-κB in triple negative breast cancer (TNBC). We profile EZH2 and NF-κB factor co-localization and positive gene regulation genome-wide, and define a subset of NF-κB targets and genes associated with oncogenic functions in TNBC that is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified transactivation domain (TAD) which mediates EZH2 recruitment to, and activation of certain NF-κB-dependent genes, and supports downstream migration and stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-κB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-κB-dependent regulatory mechanisms.
组蛋白甲基转移酶EZH2在PRC2依赖性基因抑制的背景下得到了最广泛的研究。越来越多的证据表明，EZH2在癌症背景下具有非经典功能，包括通过与转录因子相互作用促进矛盾的基因表达，如在三阴性乳腺癌（TNBC）中与NF-κB相互作用。我们在全基因组范围内分析了EZH2和NF-κB因子的共定位以及阳性基因调控，并确定了TNBC中与致癌功能相关的NF-κB靶标和基因子集，这些子集在患者数据集中富集。我们证明了EZH2和RelA之间的相互作用需要最近鉴定的反式激活域（TAD），该域介导EZH2募集到某些NF-κB依赖性基因并激活这些基因，并支持TNBC细胞中的下游迁移和干性表型。有趣的是，EZH2-NF-κB对基因和干性的正向调控不需要PRC2。这项研究通过不依赖PRC2且依赖NF-κB的调控机制，为EZH2在乳腺癌中的促癌调控功能提供了新的见解。
