An autoregulatory loop between NRF2 and HIPK2 shapes cytoprotective responses

  • Laura Torrente Fernandez

    Student thesis: Doctoral ThesisDoctor of Philosophy


    Cancer cells are constantly subjected to elevated levels of reactive oxygen species, resulting from various endogenous sources (i.e. increased metabolic activity and mitochondrial dysfunction) and external inputs such as the exposure to chemotherapeutic agents. The ability of cancer cells to adapt and overcome these challenging scenarios will determine response to treatment and thus outcome.

    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. Given the role of HIPK2 activating pro-apoptotic pathways in response to genotoxic stress, substantial effort has been dedicated towards defining the beneficial effects of re-activating/enhancing its function to sensitise cancer cells to chemotherapeutic agents. In contrast, recent studies suggest that HIPK2 can also contribute to tumour progression, although the underlying mechanisms remain unknown. Our study was focused on understanding the role of HIPK2 in the oxidative stress response, as it might have important implications in cancer development and therapy. Several reports suggest that HIPK2 can regulate the expression of antioxidant genes. However, the mechanisms linking HIPK2 to antioxidant gene expression are poorly understood.

    Nuclear factor (erythroid-derived 2)-like 2, known as NFE2L2 (gene) or NRF2 (protein), is the primary cellular barrier to counteract the deleterious effects of oxidative stress. NRF2 is a transcription factor that regulates the basal and inducible expression of hundreds of cytoprotective genes to enable cells to adapt and survive. Not surprisingly, NRF2 is often aberrantly hyperactivated in many cancer types, especially in the lungs, where oxidative damage plays a critical role in the development of many pathophysiological conditions.

    Therefore, we studied whether NRF2 regulates HIPK2 under oxidative stress conditions and whether HIPK2 regulates the expression of cytoprotective genes via NRF2. We have identified a novel crosstalk between HIPK2 and 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 vitro and in vivo. In regard to cancer treatment, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2.
    Date of Award2017
    Original languageEnglish
    SupervisorLaureano de la Vega (Supervisor)

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