Abstract
Amplification of squamous cell carcinoma-related oncogene (SCCRO) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of SCCRO requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO function remains to be defined. We found that the UBA domain of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits the neddylation activity of SCCRO in vivo by inhibiting SCCRO-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of SCCRO that reduces binding to polyubiquitin chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of SCCRO function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of SCCRO suggests that mutations may be a mechanism of oncogene activation in human cancers.
Highlights
squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1 is commonly amplified in squamous cell carcinomas
Hydrophobic residues that are critical for interactions with ubiquitin chains in structurally related domains are highly conserved in the UBA domain of SCCRO (Fig. 1A)
Our results show that the UBA domain of SCCRO is best included in the class 4 subgroup, it does not bind to monoubiquitin
Summary
SCCRO/DCUN1D1 is commonly amplified in squamous cell carcinomas. the SCCRO PONY domain is required for its function, the contribution of its UBA domain is undefined. Results: Binding of polyubiquitin chains to UBA domain inhibits SCCRO-promoted neddylation and oncogenic activity. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. We show that binding of polyubiquitin chains to the UBA domain inhibits the activity of SCCRO, a core protein in the ubiquitin-proteasome pathway. In this role, the UBA domain serves as a feedback regulator of the in vivo neddylation and oncogenic activity of SCCRO. Given the conserved binding characteristics of the UBA domain, targeting it may have therapeutic benefit in the treatment of human cancer
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