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||(missing name)|
|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|