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

Moreno, R., Banerjee, S., Jackson, A. W., Quinn, J. , Baillie, G., Dixon, J. E., Dinkova-Kostova, A. T., Edwards, J. and 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), pp. 1563-1578. (doi: 10.1038/s41418-020-00686-8) (PMID:33268814)

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.

• Item Type: Articles
• Additional Information: We are extremely grateful to the Medical Research Institute of the University of Dundee, Cancer Research UK (C52419/A22869) (LV) and (CRUK/A18644) (ADK), Mary Kay Ash Breast Cancer grant 047.16 (JED) and UCSD Moores Cancer Centre Translational and Clinical Pilot Project award 2018 (JED) for financial support.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Quinn, Dr Jean and Edwards, Professor Joanne
• Authors: Moreno, R., Banerjee, S., Jackson, A. W., Quinn, J., Baillie, G., Dixon, J. E., Dinkova-Kostova, A. T., Edwards, J., and de la Vega, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Differentiation
• Publisher: Springer Nature
• ISSN: 1350-9047
• ISSN (Online): 1476-5403
• Published Online: 02 December 2020
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cell Death and Differentiation 28(5):1563-1578
• Publisher Policy: Reproduced under a Creative Commons License