Invasion, metastasis and therapy resistance are the major cause of cancer‐associated deaths, and the EMT‐inducing transcription factor ZEB1 is a crucial stimulator of these processes. While work on ZEB1 has mainly focused on its role as a transcriptional repressor, it can also act as a transcriptional activator. To further understand these two modes of action, we performed a genome‐wide ZEB1 binding study in triple‐negative breast cancer cells. We identified ZEB1 as a novel interactor of the AP‐1 factors FOSL1 and JUN and show that, together with the Hippo pathway effector YAP, they form a transactivation complex, predominantly activating tumour‐promoting genes, thereby synergising with its function as a repressor of epithelial genes. High expression of ZEB1, YAP, FOSL1 and JUN marks the aggressive claudin‐low subtype of breast cancer, indicating the translational relevance of our findings. Thus, our results link critical tumour‐promoting transcription factors: ZEB1, AP‐1 and Hippo pathway factors. Disturbing their molecular interaction may provide a promising treatment option for aggressive cancer types.

中文翻译：

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EMT转录因子ZEB1与YAP和AP-1在乳腺癌中的全基因组合作。

侵袭，转移和治疗抗性是癌症相关死亡的主要原因，而EMT诱导转录因子ZEB1是这些过程的关键刺激因素。尽管有关ZEB1的研究主要集中在其作为转录阻遏物的作用上，但它也可以充当转录激活物。为了进一步了解这两种作用方式，我们在三阴性乳腺癌细胞中进行了全基因组ZEB1结合研究。我们将ZEB1鉴定为AP-1因子FOSL1和JUN的新型相互作用物，并表明它们与河马途径效应子YAP一起形成反式激活复合物，主要激活促肿瘤基因，从而与其协同作用成为抑癌基因。上皮基因。ZEB1，YAP，FOSL1和JUN的高表达标志着侵略性克拉丁蛋白低的亚型，指出我们发现的翻译意义。因此，我们的结果与重要的促肿瘤转录因子：ZEB1，AP-1和Hippo通路因子相关。扰乱它们的分子相互作用可能为侵略性癌症类型提供有希望的治疗选择。