Handling Editor: Tatsushi Igaki
ABSTRACT
Peptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.
This article has an associated First Person interview with the first author of the paper.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: A.B., P.S.; Methodology: A.B., P.S.; Validation: A.T., B.A., N.P.; Formal analysis: T.A.Q.; Investigation: A.B., T.A.Q., H.-W.T., N.M., V.S.; Resources: A.T., B.A., N.P., P.S.; Data curation: A.B.; Writing - original draft: A.B., P.S.; Writing - review & editing: N.P.; Visualization: A.B., P.S.; Supervision: A.B., P.S.; Funding acquisition: A.B.
Funding
This study was supported by the Wellcome Trust DBT India Alliance (IA/E/13/1/501271 to A.B.). Work in the N.P. laboratory is supported by the Howard Hughes Medical Institute.
Data availability
The LC-MS/MS reads for unlabeled proteomics generated in this study are available at the MassIVE repository (https://massive.ucsd.edu) and can be accessed using MSV000084841.
Supplementary information
Supplementary information available online at https://dmm.biologists.org/lookup/doi/10.1242/dmm.044420.supplemental
- Received February 17, 2020.
- Accepted May 27, 2020.
- © 2020. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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