TWIST1诱导上皮-间质转化（EMT），推动癌症转移。目前尚不清楚是什么决定了TWIST1功能的激活或抑制转录。我们发现，TWIST1 N-末端对抗了TWIST1调节的基因表达、癌症生长和转移。TWIST1通过其N-末端与NuRD复合物和NuA4/TIP60复合物（TIP60-Com）相互作用。未乙酰化的TWIST1-K73/76选择性地与NuRD相互作用并招募NuRD以抑制上皮靶基因的转录。二乙酰化的TWIST1-acK73/76与BRD8结合，BRD8是TIP60-Com的一个组成部分，也结合到histone H4-acK5/8上，以招募TIP60-Com来激活间质目标基因和MYC。BRD8的沉默废除了TWIST1和TIP60-Com的相互作用，以及TIP60-Com对TWIST1激活基因的招募，导致TWIST1激活的靶基因表达和癌症转移的减少。TWIST1/NuRD和TWIST1/TIP60-Com复合物都是TWIST1以最大能力促进EMT、增殖和转移所需的。因此，TWIST1-K73/76的二乙酰化状态决定了TWIST1与NuRD抑制上皮基因相互作用，还是与TIP60-Com激活间质基因和MYC相互作用。由于BRD8对TWIST1-acK73/76和TIP60-Com的相互作用至关重要，靶向BRD8可能成为抑制TWIST1激活基因表达的手段。© 2023 The Authors.

TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to TWIST1-activated genes, resulting in decreasing TWIST1-activated target gene expression and cancer metastasis. Both TWIST1/NuRD and TWIST1/TIP60-Com complexes are required for TWIST1 to promote EMT, proliferation, and metastasis at full capacity. Therefore, the diacetylation status of TWIST1-K73/76 dictates whether TWIST1 interacts either with NuRD to repress epithelial genes, or with TIP60-Com to activate mesenchymal genes and MYC. Since BRD8 is essential for TWIST1-acK73/76 and TIP60-Com interaction, targeting BRD8 could be a means to inhibit TWIST1-activated gene expression.© 2023 The Authors.