YAP and TAZ are two closely related transcriptional regulators involved in tissue growth, stem cell maintenance and cancer. YAP/TAZ are aberrantly activated in different tumors where they have causative roles in initiation, progression and metastasis. However, the transcriptional program they activate in cancer cells remains incompletely understood.
Therefore, we tried to dissect YAP/TAZ direct target genes in a breast cancer cell line (MDAMB-231 cells) by genome-wide analysis. In so doing, we discovered that YAP/TAZ mainly bind distal enhancers that contact target promoters through chromatin looping to activate a broad transcriptional program activating cell proliferation. We assessed that YAP/TAZ exploit TEAD proteins as DNA binding partners in breast cancer cells.
We then focused on the interaction of YAP/TAZ and TEAD with general transcriptional regulators, aiming at identifying indispensible co-factors for YAP/TAZ/TEAD transcriptional activity at enhancers. Our findings provide new details on YAP/TAZ behaviour, and open a new therapeutic perspective to achieve pharmacological inhibition of YAP/TAZ by impairing their nuclear function.
Part of this work has been published in Nature Cell Biology (Zanconato et al., 2015). Part is unpublished.