Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides

Abstract

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.

Mechanisms of Hippo pathway regulation

“…Both basic and clinical cancer research has implicated a role of YAP and TAZ in cancer initiation and development through suppressing cell apoptosis and promoting cell prolifieration (Moroishi et al 2015a). Concordantly, YAP and TAZ have been considered as therapeutic targets for a number of cancers (Liu-Chittenden et al 2012;Jiao et al 2014;Yu et al 2014;Zhou et al 2015b) as well as several other diseases . Notably, the R331W missense mutation of YAP has recently been linked to a germline risk in lung adenocarcinoma (Chen et al 2015a).…”

Peptide 17, an inhibitor of YAP/TEAD4 pathway, mitigates lung cancer malignancy

“…Mechanistically, when the Hippo pathway is inactivated, YAP interacts with transcriptional enhancer activation domain (TEAD) family members to promote cellular proliferation and inhibit apoptosis [11,12]. Given the critical role of YAP in lung cancer, peptide 17, a promising inhibitor of YAP/TEAD4 signaling, was supposed to ameliorate the malignancy of lung cancer [13,14].…”

MicroRNA-186 targets Yes-associated protein 1 to inhibit Hippo signaling and tumorigenesis in hepatocellular carcinoma

“…Cells (1x10 5 ) transfected with mirVana miRNA mimic negative control #1 and has-miR-186 were seeded into six-well plates following transfection. A linear wound was carefully made using a 100 µl sterile pipette tip across the confluent cell monolayer, and the cell debris was removed by washing with phosphate.…”

“…Cell invasion assay was performed in a 24-well plate with 8 µm pore size chamber inserts (BD Biosciences, Franklin Lakes, NJ, USA). Cells (1x10 5 ) transfected with mirVana miRNA mimic negative control #1 and has-miR-186 were placed into the upper chamber of each well with Matrigel-coated membrane, which was diluted with serum-free culture medium. The lower compartment was filled with 500 µl medium containing 10% fetal bovine serum as a chemo-attractant.…”

“…When the upstream effectors are activated they recruit YAP1-TAZ complex, which is transferred into the nucleus to interact with TEADs, and drives target gene expression to promote cell proliferation and suppress apoptosis (3). The disruption of YAP1-TEAD interaction by YAP-like peptides leads to a significant decrease in the tumor growth rate (4,5). The overexpression of YAP1 in transgenic mice was observed to lead to liver outgrowth and HCC (6).…”