ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP

Francesca Bufalieri, Paola Infante, Flavia Bernardi, Miriam Caimano, Paolo Romania, Marta Moretti, Ludovica Lospinoso Severini, Julie Talbot, Ombretta Melaiu, Mirella Tanori, Laura Magno, Diana Bellavia, Carlo Capalbo, Stéphanie Puget, Enrico Smaele, Gianluca Canettieri, Daniele Guardavaccaro, Luca Busino, Angelo Peschiaroli, Simonetta Pazzaglia, Giuseppe Giannini, Gerry Melino, Franco Locatelli, Alberto Gulino, Olivier Ayrault, Doriana Fruci () and Lucia Marcotullio ()
Additional contact information
Francesca Bufalieri: University La Sapienza
Paola Infante: Istituto Italiano di Tecnologia
Flavia Bernardi: University La Sapienza
Miriam Caimano: University La Sapienza
Paolo Romania: Ospedale Pediatrico Bambino Gesù, IRCCS
Marta Moretti: University La Sapienza
Ludovica Lospinoso Severini: University La Sapienza
Julie Talbot: Institut Curie, PSL Research University, CNRS UMR, INSERM
Ombretta Melaiu: Ospedale Pediatrico Bambino Gesù, IRCCS
Mirella Tanori: l’Energia e lo Sviluppo Economico Sostenibile (ENEA)
Laura Magno: Istituto Italiano di Tecnologia
Diana Bellavia: University La Sapienza
Carlo Capalbo: University La Sapienza
Stéphanie Puget: Necker University Hospital, University Paris Descartes, Sorbonne Paris Cité
Enrico Smaele: University La Sapienza
Gianluca Canettieri: University La Sapienza
Daniele Guardavaccaro: University of Verona
Luca Busino: Perelman School of Medicine, University of Pennsylvania
Angelo Peschiaroli: Institute of Translational Pharmacology (IFT)
Simonetta Pazzaglia: l’Energia e lo Sviluppo Economico Sostenibile (ENEA)
Giuseppe Giannini: University La Sapienza
Gerry Melino: University of Cambridge
Franco Locatelli: Ospedale Pediatrico Bambino Gesù, IRCCS
Alberto Gulino: University La Sapienza
Olivier Ayrault: Institut Curie, PSL Research University, CNRS UMR, INSERM
Doriana Fruci: Ospedale Pediatrico Bambino Gesù, IRCCS
Lucia Marcotullio: University La Sapienza

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract The Hedgehog (Hh) pathway is essential for embryonic development and tissue homeostasis. Aberrant Hh signaling may occur in a wide range of human cancers, such as medulloblastoma, the most common brain malignancy in childhood. Here, we identify endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a previously unknown player in the Hh signaling pathway. We demonstrate that ERAP1 binds the deubiquitylase enzyme USP47, displaces the USP47-associated βTrCP, the substrate-receptor subunit of the SCFβTrCP ubiquitin ligase, and promotes βTrCP degradation. These events result in the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. Remarkably, genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Our findings unveil an unexpected role for ERAP1 in cancer and indicate ERAP1 as a promising therapeutic target for Hh-driven tumors.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-11093-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11093-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-11093-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().