JRK is a positive regulator of beta-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer
The loss of beta-catenin inhibitory components is a well-established mechanism of carcinogenesis but beta-catenin hyperactivity can also be enhanced through its coactivators. Here we first interrogated a highly validated genomic screen and the largest repository of cancer genomics data and identified JRK as a potential new oncogene and therapeutic target of the beta-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a beta-catenin activator function, depletion of JRK in several cancer cell lines repressed beta-catenin transcriptional activity and reduced cell proliferation. Importantly, JRK expression was aberrantly elevated in 21% of colorectal cancers, 15% of breast and ovarian cancers and was associated with increased expression of beta-catenin target genes and increased cell proliferation. This study shows that JRK is required for beta-catenin hyperactivity regardless of the adenomatous polyposis coli/beta-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer.
|ISBN||1476-5594 (Electronic) 0950-9232 (Linking)|
|Authors||Pangon, L.; Ng, I.; Giry-Laterriere, M.; Currey, N.; Morgan, A.; Benthani, F.; Tran, P. N.; Al-Sohaily, S.; Segelov, E.; Parker, B. L.; Cowley, M. J.; Wright, D. C.; St Heaps, L.; Carey, L.; Rooman, I.; Kohonen-Corish, M. R.;|
|Responsible Garvan Author|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26455321|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13264|