Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-11093-0
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Funding
- Associazione Italiana Ricerca Cancro (AIRC) [IG14723, IG20801, IG18495, IG17575, IG17734]
- Progetti di Ricerca di Universita Sapienza di Roma, Italian Ministry of Health [PRIN 2012C5YJSK_002, PRIN 2017BF3PXZ_003, PE-2011-02351866]
- Italian Ministry of Education, Universities and Research Dipartimenti di Eccellenza [L. 232/2016]
- Pasteur Institute/Cenci Bolognetti Foundation
- Istituto Italiano di Tecnologia (IIT)
- PhD Degree Program in Biotechnology in Clinical Medicine, University of Rome La Sapienza
- MRC [MC_UU_00025/2, MC_U132670600] Funding Source: UKRI
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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 beta TrCP, the substrate-receptor subunit of the SCF beta TrCP ubiquitin ligase, and promotes beta TrCP 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.
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