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.
Highlights
Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases, and it modulates cell proliferation, differentiation, apoptosis and development.[1,2,3,4,5,6,7] HIPK2 responds to a variety of physiological stresses,[3,8,9,10,11,12] transforming these cues into changes in transcriptional programs, which in turn enables cells to adapt to and survive the original insult
We found that NRF2 knockout cells (NRF2-KO) have reduced protein and messenger RNA basal levels of HIPK2; NRF2 reconstitution restored both the protein and the mRNA levels of HIPK2 (Figure 1a)
We confirmed the effect of NRF2 on HIPK2 mRNA levels, first by using different NRF2-KO cell lines (Supplementary Figures S1B and S1C) and second, by using various short hairpin RNA against NRF2 (Supplementary Figure S1D)
Summary
Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases, and it modulates cell proliferation, differentiation, apoptosis and development.[1,2,3,4,5,6,7] HIPK2 responds to a variety of physiological stresses,[3,8,9,10,11,12] transforming these cues into changes in transcriptional programs, which in turn enables cells to adapt to and survive the original insult. We found that NRF2 activators increase both mRNA and protein levels of HIPK2 in H1299 cells (lung cancer cells with functional KEAP1), and that this induction requires NRF2 (Figure 1b).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
