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

Rita Moreno Dorta, Sourav Banerjee, Angus W. Jackson, Jean Quinn, Gregg Baillie, Jack E. Dixon, Albena Dinkova-Kostova, Joanne Edwards, Laureano de la Vega (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalCell Death & Differentiation
Volume0
Early online date2 Dec 2020
DOIs
Publication statusE-pub ahead of print - 2 Dec 2020

Keywords

  • DYRK2
  • Proteotoxic stress
  • HSF1
  • Triple-Negative Breast Cancer
  • non-oncogene addiction

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