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.
Childhood cancers are one of the most cause of death infants older than 1 year in the developed world (Ward et al, 2014; WHO, 2015). Because pediatric tumors arise early in the life, they result in a grievous loss-of quality-adjusted-life-years, due to the disabling consequences of treatment in surviving patients (Ivanov et al, 2016).
While leukemia is the commonest childhood cancers accounting for 30% of pediatric tumors, brain and central nervous system malignancies are the most frequent in the solid tumor group making up 20% of childhood cancers (Ward et al, 2014).
Medulloblastoma (MB) is considered the most common brain malignant childhood cancer and aberrant activation of HH pathway is responsible for the occurrence of about 30% of cases. Current treatments including surgery, cranio-spinal radiation and high-dose chemotherapy have led to improvement in survival, but most treated patients suffer devastating side effects. Other current treatment options largely target SMO, but they have demonstrated limitations such as drug resistance due to acquired SMO mutations or oncogenic mutations downstream this receptor (Huang eta al, 2015).
The need to develop less invasive and toxic therapies and overcome the problem of drug resistance for the HH-MB treatment represents for the research an important goal that can be pursued deepening the study of the mechanisms that regulate this signaling. Therefore, our findings defining the regulation of ERAP1 and identifying TRIM21 as a new molecular player involved in the regulation of HH pathway, will be able to increase the knowledge about the developmental and tumorigenesis processes in which this signaling is implicated.