Abstract
ABSTRACTPeptide 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.
Highlights
Drosophila has emerged as an effective tumor model for the screening of small-molecule therapeutics (Dar et al, 2012; Khoo et al, 2013; Markstein et al, 2014; Bangi et al, 2016)
The TEA/ATTS domain-containing TEAD proteins are a class of transcription factors (TFs) that regulate YAP-induced proliferation and drive differentiation programs of VGLLs on the other (Gibault et al, 2018; Huh et al, 2019)
In this study, using Yki-driven intestinal stem cell (ISC) tumors, we document in vivo inhibition of Yki-driven ISC tumor progression (Fig. 4I) by oral uptake of a Drosophila Vg-derived TONDU peptide
Summary
Drosophila has emerged as an effective tumor model for the screening of small-molecule therapeutics (Dar et al, 2012; Khoo et al, 2013; Markstein et al, 2014; Bangi et al, 2016). Whereas cancer-promoting misregulated kinases are amenable to inhibition by small molecules, others, such as transcription factors (TFs) and co-factors, are largely considered undruggable (Bhagwat and Vakoc, 2015; Lambert et al, 2018). In this regard, peptides are attractive as therapeutic molecules (Lau and Dunn, 2018; Drucker, 2019) because of their high selectivity, improved tolerance and ability to target large interacting interfaces (Furet et al, 2019). A synthetic peptide analog of the TONDU domain of VGLL4 was found to inhibit gastric cancer growth (Jiao et al, 2014) in a mouse xenograft model
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