Ricerc@Sapienza

The Hedgehog (HH) pathway is a crucial signaling that controls embryonic development and tissue homeostasis. Inappropriate activation of the HH pathway may occur in a wide spectrum of cancers, such as medulloblastoma (MB), the most common and aggressive pediatric brain malignancy that arises in the cerebellum. Recently, we identified the endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a strong activator of the HH pathway, representing a promising druggable target for HH-driven tumors treatment. Indeed, our findings unveil the oncogenic properties of ERAP1 in HH-dependent MB (HH-MB) and demonstrate that its inhibition significantly impairs HH-dependent cancer growth. To further elucidate the molecular mechanism implicated in the regulation of ERAP1 in HH-MB tumorigenesis, we investigated the potential binding partners of this enzyme by proteomic analysis. Among the emerged interactors, we focused our attention on the Tripartite motif-containing protein 21 (TRIM21), a cytosolic E3 ubiquitin ligase and antibody receptor, well known to be involved in the immune response. Our compelling preliminary results strongly suggest that TRIM21/ERAP1 interaction promotes protein stabilization and/or activity of ERAP1, thus increasing the HH pathway activity.
The main aim of this proposal is the characterization of the interplay between ERAP1 and TRIM21 to further refine the scenario of molecular players involved in the regulation of HH signaling and to develop more accurate targeted strategies to impair the aberrant activation of the HH pathway in cancer.