PT  - JOURNAL ARTICLE
AU  - Yao Yuan
AU  - Natalia Salinas Parra
AU  - Qianming Chen
AU  - Ramiro Iglesias-Bartolome
TI  - YAP1-TAZ/TEAD transcriptional networks restrain differentiation downstream of oncogenic Hedgehog-SMO activity
AID  - 10.1101/2020.12.28.424593
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.28.424593
4099  - http://biorxiv.org/content/early/2020/12/28/2020.12.28.424593.short
4100  - http://biorxiv.org/content/early/2020/12/28/2020.12.28.424593.full
AB  - 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, by comparing the effects of YAP1/TAZ knockdown with those resulting from TEAD blockage, we unveil the consequences of YAP1/TAZ transcriptional inhibition in cancer cells. 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) driven by the smoothened oncogene (SmoM2), TEADi and YAP1/TAZ knockdown lead to reduced proliferation and increased differentiation of tumor cells both in vitro and in vivo. We find that TEAD transcriptional networks inactivate differentiation in BCC by regulating KLF4. Furthermore, we determine YAP1/TAZ TEAD-independent effects in cancer cells that impact Stat3 and NF-κB gene networks. Our results reveal the TEAD dependent and independent roles of YAP1/TAZ in cancer and expose potential pitfalls for targeting TEAD transcription in tumors.Competing Interest StatementThe authors have declared no competing interest.