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

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Bufalieri, Francesca  ORCID logo
Infante, Paola 
Bernardi, Flavia 
Caimano, Miriam 
Romania, Paolo 

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.

Aminopeptidases, Animals, Carcinogenesis, Hedgehog Proteins, Mice, Minor Histocompatibility Antigens, NIH 3T3 Cells, Protein Stability, Proteolysis, Signal Transduction, Ubiquitin-Specific Proteases, beta-Transducin Repeat-Containing Proteins
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Nat Commun
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Springer Science and Business Media LLC