Transcriptional repressor turns into an activator in aggressive cancers

Transcriptional repressor turns into an activator in aggressive cancers

In the past decade it became evident that, like in leukemia, also in most solid cancers, a subpopulation of tumour cells termed cancer stem cells (CSCs) has high tumor-initiating capacity and is the source of metastasis and treatment relapse. Notably, it has been demonstrated that the embryonic epithelial– mesenchymal transition (EMT)-program can be activated in cancer cells, which not only induces an aberrant motility triggering dissemination and metastasis, but also confers stemness properties resulting in a migrating CSC-phenotype.

The program is activated by EMT-inducing transcription factors including members of the Snail-, Twist- and ZEB families5. The EMT-activator ZEB1 turned out to be particularly potent. ZEB1 is associated with aggressive behaviour, metastasis, treatment resistance and poor prognosis in different tumor types, including breast, pancreatic and lung cancer.

Mechanistically, ZEB1 is a transcriptional repressor of epithelial genes, for example, for E-cadherin and cell polarity factors, thereby stimulating an undifferentiated and highly motile phenotype. This property of ZEB1 is considered important for metastasis as shown in many model systems. By repressing the expression of the stemness-inhibiting microRNAs miR-200 and miR-203, ZEB1 can also confer stemness properties, thereby linking motility and stemness towards a migrating cancer stem cell phenotype. Moreover ZEB1, likely through its stemness-promoting effect, can confer survival and therapy resistance, as shown for many different cancer types, such as pancreatic, breast and lung cancer.

Owing to these pleiotropic effects, ZEB1 is considered the central factor for high cancer cell plasticity as a motor towards aggressive, metastatic and therapy-resistant cancer types. However, the strong effects of ZEB1 cannot be solely explained by the ascribed functions as a transcriptional repressor.

In this study, by analysing ZEB1-dependent gene expression patterns, authors demonstrate mechanistic links explaining the extraordinary potency of ZEB1 in driving tumor progression. They describe a direct interaction between ZEB1 and the Hippo pathway effector YAP, shifting ZEB1 from a repressor to a transcriptional activator and thereby linking two pathways with very similar cancerpromoting effects.

Notably, ZEB1 directly binds to YAP, but not to the paralogue factor TAZ. Functional cooperation of ZEB1 and YAP stimulates the transcriptional activation of a ‘common ZEB1/YAP target gene set’.

This gene set is a predictor of poor survival, therapy resistance and increased metastatic risk in hormone receptor-negative breast cancer, indicating the clinical relevance of these findings.