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JRK is a positive regulator of β-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer

Oncogene volume 35, pages 2834–2841 (2016)Cite this article

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Abstract

The loss of β-catenin inhibitory components is a well-established mechanism of carcinogenesis but β-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 β-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a β-catenin activator function, depletion of JRK in several cancer cell lines repressed β-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 β-catenin target genes and increased cell proliferation. This study shows that JRK is required for β-catenin hyperactivity regardless of the adenomatous polyposis coli/β-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer.

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Acknowledgements

We thank the South Western Sydney Colorectal Tissue Bank for the colorectal cancer patient specimens and Dr Christopher Henderson (Liverpool Hospital, Sydney, Australia) for helping with immunohistochemistry scoring. β-Catenin constructs were a gift from A/Prof Beric Henderson (Westmead Institute for Cancer Research, Westmead Millennium Institute, Sydney, Australia). JRK-FLAG and TCf7L2 constructs were a gift from Dr Benchabane (Department of Genetics and the Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA). The M50 Super 8x TOPFlash and M51 Super 8x FOPFlash reporter constructs were obtained from Addgene and originally provided by Prof Randall Moon (University of Washington, Seattle, Washington). This work was supported by grants from the National Health and Medical Research Council of Australia (GNT1020406), Cure Cancer Australia/Cancer Australia (1049846), Cancer Institute NSW (13ECF1-46) and Cancer Institute NSW (10CDF232). The contents of the published material are solely the responsibility of the administering institution, participating institutions or individual authors and do not reflect the views of NHMRC.

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Author notes

  1. L Pangon and I Ng: These authors contributed equally to this work.

Authors and Affiliations

  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia

    L Pangon, I Ng, M Giry-Laterriere, N Currey, A Morgan, F Benthani, P N Tran, S Al-Sohaily, M J Cowley, I Rooman & M R J Kohonen-Corish

  2. St Vincent’s Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia

    L Pangon, F Benthani, E Segelov, M J Cowley, I Rooman & M R J Kohonen-Corish

  3. Biological Mass Spectrometry Unit, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia

    B L Parker

  4. Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales, Australia

    B L Parker

  5. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia

    M J Cowley

  6. Cytogenetics, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia

    D C Wright, L St Heaps & L Carey

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  1. L Pangon
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Correspondence to L Pangon.

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Pangon, L., Ng, I., Giry-Laterriere, M. et al. JRK is a positive regulator of β-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer. Oncogene 35, 2834–2841 (2016). https://doi.org/10.1038/onc.2015.347

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