Huang G, Towe CW, Choi L, Yonekawa Y, Bommelje CC, Bains S, Rechler W, Hao B, Ramanathan Y, Singh B

Amplification of SCCRO activates its function as an oncogene in a wide range of human cancers. SCCRO's oncogenic activity requires its PONY domain, which regulates its E3 activity for neddylation. Contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO's function remains to be defined. We found that the UBA domain ...

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of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits SCCRO's neddylation activity 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 mutation in UBA domain of SCCRO that reduces binding to polyubiquitin chains significantly enhances its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frame-shift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas (TCGA) showed that recurrent mutations cluster in the UBA domains of SCCRO, lose binding 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.

Date: Nov. 19, 2014

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