Rabbit Anti-Human URI1 Polyclonal antibody

Objectives. Readily apparent cyclin El expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1(hi) to subset has intact BRCA1/2, unfavorable outcome, and is potentially therapeutically targetable. We studied whether non-amplified/cyclin E1(hi) HGSOC has similar characteristics. We also assessed the expression of cyclin El degradation-associated proteins, FBXW7 and USP28, as potential drivers of high cyclin El expression in both subsets. Methods. 262 HGSOC cases were analyzed by in situ hybridization for 19q12 locus amplification and immunohistochemistry for cyclin El, URI1 (another protein encoded by the 19812 locus), FBXW7 and USP28 expression. Tumors were classified by 19q12 amplification status and correlated to cyclin El and URI1 expression, BRCA1/2 germline mutation, FBXW7 and USP28 expression, and clinical outcomes. Additionally, we assessed the relative genomic instability of amplified/cyclin E1(hi) and non-amplified/cyclin E1(hi) groups of HGSOC datasets from The Cancer Genome Atlas. Results. Of the 82 cyclin El hi cases, 43 (52%) were amplified and 39 (48%) were non-amplified. Unlike amplified tumors, non-amplified/cyclin E1(hi) tumor status was not mutually exclusive with gBRCA1/2 mutation. The non-amplified/cyclin E1(hi) group had significantly increased USP28, while the amplified/cyclin E1(hi) cancers had significantly lower FBXW7 expression consistent with a role for both in stabilizing cyclin E1. Notably, only the amplified/cyclin E1(hi) subset was associated with genomic instability and had a worse outcome than nonamplified/cyclin E1(hi) group. Conclusions. Amplified/cyclin E1(hi) and non-amplified/cyclin E1(hi) tumors have different pathological and biological characteristics and clinical outcomes indicating that they are separate subsets of cyclin E1(hi) HGSOC. (C) 2018 Published by Elsevier Inc.

Chaperone dependency of cancer cells is an emerging trait that relates to the need of transformed cells to cope with the various stresses associated with the malignant state. URI1 (unconventional prefoldin RPB5 interactor 1) encodes a member of the prefoldin (PFD) family of molecular chaperones that acts as part of a heterohexameric PFD complex, the URI1 complex (URI1C), to promote assembly of multiprotein complexes involved in cell signaling and transcription processes. Here, we report that human colorectal cancer (CRCs) cell lines demonstrate differential dependency on URI1 and on the URI1 partner PFD STAP1 for survival, suggesting that this differential vulnerability of CRC cells is directly linked to URI1C chaperone function. Interestingly, in URI1-dependent CRC cells, URI1 deficiency is associated with non-genotoxic p53 activation and p53-dependent apoptosis. URI1-independent CRC cells do not exhibit such effects even in the context of wildtype p53. Lastly, in tumor xenografts, the conditional depletion of URI1 in URI1-dependent CRC cells was, after tumor establishment, associated with severe inhibition of subsequent tumor growth and activation of p53 target genes. Thus, a subset of CRC cells has acquired a dependency on the URI1 chaperone system for survival, providing an example of 'non-oncogene addiction' and vulnerability for therapeutic targeting.