Ricerc@Sapienza

YAP (Yes-associated protein) is a transcriptional co-factor regulating a number of genes involved in several cellular processes, including proliferation, stemness and Epithelial-to-Mesenchymal Transition. Although the current model postulates that YAP activity is largely dependent on the transcriptional factors belonging to TEAD family, mounting evidence indicates that YAP may use other DNA-binding partners and that formation of specific transcriptional complexes and their regulation can be cell- and context- dependent and drive specific cellular outcomes. This is relevant in cancer, where the dynamics of the genome occupancy and the specific gene expression could differently influence tumor progression. Our published and preliminary data suggest that STAT3 could be a new transcriptional partner of YAP and that ERK5 represents a new YAP regulator. We have demonstrated in liver cells a physical interaction between YAP and STAT3 and their co-occupancy of promoter of Snail, master gene of EMT. Moreover, we found that ERK5 activity is required for this interaction. Starting from these data and from our analysis of publicly available ChIP-seq datasets for YAP and STAT3 obtained from a cell model of Triple Negative Breast Cancer enforcing our working hypothesis, this project aims to characterize the activity and the regulation of YAP/STAT3 complex in TNBC, a tumor resistant to therapy and with an overall bad prognosis.
Therefore, we will analyze: i) the cooperation of YAP and STAT3 in DNA-binding and in driving specific gene expression in TNBC cells, ii) the role of the YAP/STAT3 complex in cell motility and tumor progression, iii) the regulation of its activity by ERK5 and the molecular mechanisms involved. These studies will allow to clarify the molecular mechanisms underlying the different YAP-induced cellular outcomes and to provide new insights in the regulation of YAP activity in TNBC, in the attempt to suggest new molecular targets for therapeutic treatments.