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Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides
Author(s) -
Zhou Zheng,
Hu Taishan,
Xu Zhiheng,
Lin Zhaohu,
Zhang Zhisen,
Feng Teng,
Zhu Liangcheng,
Rong Yiping,
Shen Hong,
Luk John M.,
Zhang Xiongwen,
Qin Ning
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-262980
Subject(s) - hippo signaling pathway , carcinogenesis , effector , microbiology and biotechnology , cancer research , enhancer , chemistry , biology , transcription factor , biochemistry , genetics , cancer , gene
Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes‐associated protein (YAP)‐transcriptional enhancer activation domain family member (TEAD) association is essential for YAP‐driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP‐like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP‐TEAD interaction in vitro . To confirm that blocking YAP‐TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant‐negative mutation (Y406H) of TEAD1 to abolish YAP‐TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP‐induced oncogenesis.—Zhou, Z., Hu, T., Xu, Z., Lin, Z., Zhang, Z., Feng, T., Zhu, L., Rong, Y., Shen, H., Luk, J. M., Zhang, X., Qin, N. Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides. FASEB J . 29, 724‐732 (2015). www.fasebj.org