Oncogenic Hedgehog-Smoothened Signaling Depends on YAP1‒TAZ/TEAD Transcription to Restrain Differentiation in Basal Cell Carcinoma

Disruption of the transcriptional activity of the Hippo pathway members YAP1 and TAZ has become a major target for cancer treatment. However, detailed analysis of the effectivity and networks affected by YAP1/TAZ transcriptional targeting are limited. Here, we utilize TEADi, an inhibitor of the binding of YAP1 and TAZ with their main transcriptional target TEAD in a mouse model of basal cell carcinoma (BCC) to unveil the consequences of YAP1/TAZ transcriptional inhibition in cancer cells. Both TEADi and YAP1/TAZ knockdown lead to reduced proliferation and increased differentiation of mouse BCC driven by oncogenic Hedgehog-Smoothened (SmoM2) activity. While TEAD transcriptional networks were essential to inactivate differentiation in BCC, this inactivation was found to be indirect and potentially mediated through the repression of KLF4 by SNAI2. By comparing the transcriptional effects of TEADi with those caused by YAP1/TAZ depletion, we determined YAP1/TAZ TEAD-independent effects in cancer cells that impact STAT3 and NF-κB. Our results reveal the gene networks affected by targeting YAP1/TAZ-TEAD in BCC tumors and expose potential pitfalls for targeting TEAD transcription in cancer.