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.
| Original language | English |
|---|---|
| Pages (from-to) | 3304 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jul 24 2019 |
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ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP. / Bufalieri, Francesca; Infante, Paola; Bernardi, Flavia; Caimano, Miriam; Romania, Paolo; Moretti, Marta; Lospinoso Severini, Ludovica; Talbot, Julie; Melaiu, Ombretta; Tanori, Mirella; Di Magno, Laura; Bellavia, Diana; Capalbo, Carlo; Puget, Stéphanie; De Smaele, Enrico; Canettieri, Gianluca; Guardavaccaro, Daniele; Busino, Luca; Peschiaroli, Angelo; Pazzaglia, Simonetta; Giannini, Giuseppe; Melino, Gerry; Locatelli, Franco; Gulino, Alberto; Ayrault, Olivier; Fruci, Doriana; Di Marcotullio, Lucia.
In: Nature Communications, Vol. 10, No. 1, 24.07.2019, p. 3304.Research output: Contribution to journal › Article
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TY - JOUR
T1 - ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP
AU - Bufalieri, Francesca
AU - Infante, Paola
AU - Bernardi, Flavia
AU - Caimano, Miriam
AU - Romania, Paolo
AU - Moretti, Marta
AU - Lospinoso Severini, Ludovica
AU - Talbot, Julie
AU - Melaiu, Ombretta
AU - Tanori, Mirella
AU - Di Magno, Laura
AU - Bellavia, Diana
AU - Capalbo, Carlo
AU - Puget, Stéphanie
AU - De Smaele, Enrico
AU - Canettieri, Gianluca
AU - Guardavaccaro, Daniele
AU - Busino, Luca
AU - Peschiaroli, Angelo
AU - Pazzaglia, Simonetta
AU - Giannini, Giuseppe
AU - Melino, Gerry
AU - Locatelli, Franco
AU - Gulino, Alberto
AU - Ayrault, Olivier
AU - Fruci, Doriana
AU - Di Marcotullio, Lucia
PY - 2019/7/24
Y1 - 2019/7/24
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-11093-0
DO - 10.1038/s41467-019-11093-0
M3 - Article
VL - 10
SP - 3304
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -