YAP Inhibits the TEAD-NF-κB Complex and Suppresses the Growth of Clear Cell Renal Cell Carcinoma

Research Background

Conventionally, the Hippo signaling pathway inhibits YAP-TEAD transcriptional complexes by keeping the transcriptional coactivator YAP phosphorylated and retained in the cytoplasm, thereby impeding tumor growth. However, researchers from Xinxiang Medical University and Shandong University Qilu Hospital have discovered that in clear cell renal cell carcinoma (CCRCC), YAP plays a tumor-suppressing role. This study suggests that activating YAP might become a new strategy for treating patients. The research, conducted by Zhongbo Li and Peng Su among others, was published in Science Signaling on July 2, 2024.

Research Methods and Findings

The researchers identified through cell culture, xenografting, and patient-derived experimental models that inhibiting the upstream Hippo pathway kinases MST1 and MST2 or expressing a constitutively active YAP mutant impeded CCRCC proliferation and reduced NF-κB-mediated gene expression. They unveiled a mechanism whereby the NF-κB subunit p65 binds with the transcriptional coactivator TEAD to promote NF-κB target gene expression and drive cell proliferation. However, YAP competes with TEAD, disrupting its interaction with NF-κB and causing p65 to dissociate from the target gene promoters, thereby inhibiting the NF-κB transcriptional program. Furthermore, pharmacological activation of endogenous YAP significantly inhibited CCRCC proliferation, migration, and invasion, with similar effects observed using the small molecule inhibitor XMU-MP-1 to activate YAP. Conversely, the elimination of YAP also suppressed CCRCC cell growth.

Research Conclusions and Significance

This study has identified the tumor-suppressive role of YAP in negating NF-κB signaling in CCRCC, providing the possibility of treating CCRCC by activating YAP. This scientific basis deepens our understanding of the multifaceted roles of YAP in cancer development and offers new strategies for cancer treatment.

Features and Highlights

The research highlights the tumor-suppressive function of YAP in clear cell renal carcinoma and proposes a novel strategy to slow tumor growth by leveraging the Hippo-YAP axis non-traditionally—through YAP activation. The research also uncovers the interaction between TEAD and NF-κB, and scientifically explains how YAP intervenes and disrupts this interaction, which is significant for developing YAP-targeted therapies.

The above is a report on the study “YAP Inhibition of the TEAD-NF-κB Complex and Its Tumor-Suppressive Effect in Clear Cell Renal Carcinoma” published in Science Signaling. This research not only reveals a new function of YAP in tumors but also provides new directions for future treatments.