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Moreno R, Banerjee S, Jackson AW, et al. The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress. Cell Death Differ. 2020;28(5):1563-1578doi: 10.1038/s41418-020-00686-8.
Moreno, R., Banerjee, S., Jackson, A. W., Quinn, J., Baillie, G., Dixon, J. E., Dinkova-Kostova, A. T., Edwards, J., & de la Vega, L. (2021). The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress. Cell death and differentiation, 28(5), 1563-1578. https://doi.org/10.1038/s41418-020-00686-8
Moreno, Rita, et al. "The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress." Cell death and differentiation vol. 28,5 (2021): 1563-1578. doi: https://doi.org/10.1038/s41418-020-00686-8
Moreno R, Banerjee S, Jackson AW, Quinn J, Baillie G, Dixon JE, Dinkova-Kostova AT, Edwards J, de la Vega L. The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress. Cell Death Differ. 2021 May;28(5):1563-1578. doi: 10.1038/s41418-020-00686-8. Epub 2020 Dec 02. PMID: 33268814; PMCID: PMC8166837.
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Cell Death Differ. 2021 May;28(5):1563-1578. doi: 10.1038/s41418-020-00686-8. Epub 2020 Dec 02.

The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress.

Cell death and differentiation

Rita Moreno, Sourav Banerjee, Angus W Jackson, Jean Quinn, Gregg Baillie, Jack E Dixon, Albena T Dinkova-Kostova, Joanne Edwards, Laureano de la Vega

Affiliations

  1. Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.
  2. Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093-0721, USA.
  3. Unit of Gastrointestinal Oncology and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK.
  4. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  5. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA.
  6. Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK. [email protected].

PMID: 33268814 PMCID: PMC8166837 DOI: 10.1038/s41418-020-00686-8

Abstract

To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target.

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