YAP represses the TEAD–NF-κB complex and inhibits the growth of clear cell renal cell carcinoma

Author:

Li Zhongbo1ORCID,Su Peng2ORCID,Yu Miao3ORCID,Zhang Xufeng4ORCID,Xu Yaning5ORCID,Jia Tianwei5ORCID,Yang Penghe1,Zhang Chenmiao1,Sun Yanan2,Li Xin1,Yang Huijie1,Ding Yinlu3ORCID,Zhuang Ting1ORCID,Guo Haiyang5ORCID,Zhu Jian6ORCID

Affiliation:

1. Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, Henan Province, P.R. China.

2. Department of Pathology, Shandong University Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, P.R. China.

3. Department of General Surgery, Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, P.R. China.

4. Kidney Transplantation, Second Hospital, Cheloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, P.R. China.

5. Department of Clinical Laboratory, Second Hospital, Cheloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, P.R. China.

6. Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning Province, PR China.

Abstract

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB–target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner—that is, by activating YAP—may be a strategy for slowing tumor growth in patients.

Publisher

American Association for the Advancement of Science (AAAS)

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