Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses

Laura Torrente, Carlos Sanchez, Rita Moreno Dorta, Sudhir Chowdhry, Paula Cabello, Kyoichi Isono, Haruhiko Koseki, Tadashi Honda, John Hayes, Albena Dinkova-Kostova, Laureano de la Vega (Lead / Corresponding author)

    Research output: Contribution to journalArticle

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    Abstract

    Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases that modulates cell growth, apoptosis, proliferation and development. HIPK2 has several well-characterised tumour suppressor roles, but recent studies suggest it can also contribute to tumour progression, although the underlying mechanisms are unknown. Herein, we have identified novel crosstalk between HIPK2 and the cytoprotective transcription factor NRF2. We show that HIPK2 is a direct transcriptional target of NRF2, identifying a functional NRF2 binding site in the HIPK2 gene locus and demonstrating for the first time a transcriptional mode of regulation for this kinase. In addition, HIPK2 is required for robust NRF2 responsiveness in cells and in vivo. By using both gain-of-function and loss-of-function approaches, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2. Our results have uncovered a new downstream effector of HIPK2, NRF2, which is frequently activated in human tumours correlating with chemoresistance and poor prognosis. Furthermore, our results suggest that modulation of either HIPK2 levels or activity could be exploited to impair NRF2-mediated signalling in cancer cells, and thus sensitise them to chemotherapeutic drugs.Oncogene advance online publication, 10 July 2017; doi:10.1038/onc.2017.221.

    Original languageEnglish
    Pages (from-to)6204-6212
    Number of pages9
    JournalOncogene
    Volume36
    Issue number44
    Early online date10 Jul 2017
    DOIs
    Publication statusPublished - 2 Nov 2017

    Keywords

    • HIPK2
    • NRF2
    • cytoprotection
    • oxidative stress
    • chemoresistance

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  • Profiles

    No photo of Laureano de la Vega

    de la Vega, Laureano

    Person: Academic

    No photo of John Hayes

    Hayes, John

    • Cellular Medicine - Professor (Teaching and Research) & Personal Chair of Molecular Carcinogenesis

    Person: Academic

    Cite this

    Torrente, L., Sanchez, C., Moreno Dorta, R., Chowdhry, S., Cabello, P., Isono, K., Koseki, H., Honda, T., Hayes, J., Dinkova-Kostova, A., & de la Vega, L. (2017). Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses. Oncogene, 36(44), 6204-6212. https://doi.org/10.1038/onc.2017.221