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

Rita Moreno1, Sourav Banerjee1,2, Angus W Jackson1

  • 1Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.

Cell Death and Differentiation
|December 3, 2020
PubMed

Insights

Dual specificity tyrosine-regulated kinase 2 (DYRK2) activates heat shock factor 1 (HSF1) in triple-negative breast cancer. Targeting DYRK2 may offer a new therapeutic strategy for TNBC by reducing HSF1 activity.

Area of Science:

  • Molecular oncology
  • Cellular stress response

Background:

  • Cancer cells activate the proteotoxic-stress response pathway, regulated by heat shock factor 1 (HSF1), to survive.
  • This pathway is crucial for cancer initiation, progression, and chemoresistance, making HSF1 an attractive therapeutic target.
  • Targeting upstream regulators of HSF1 is a viable strategy due to challenges in inhibiting transcriptional regulators directly.

Purpose of the Study:

  • To investigate the role of dual specificity tyrosine-regulated kinase 2 (DYRK2) as an upstream regulator of HSF1 in triple-negative breast cancer (TNBC).
  • To determine if DYRK2 modulates HSF1 activity and influences TNBC cell survival under proteotoxic stress.
  • To assess the clinical relevance of DYRK2 as a potential therapeutic target in TNBC.

Main Methods:

  • Investigated the interaction between DYRK2 and HSF1 in TNBC cells.
  • Assessed the effect of DYRK2 depletion on HSF1 phosphorylation, nuclear stability, and transcriptional activity.
  • Evaluated the impact of DYRK2 on TNBC cell sensitivity to proteotoxic stress.
  • Correlated DYRK2 and active HSF1 levels with patient prognosis in TNBC tumors.

Main Results:

  • DYRK2 phosphorylates HSF1 in TNBC cells, enhancing its nuclear stability and transcriptional activity.
  • Depletion of DYRK2 reduces HSF1 activity and sensitizes TNBC cells to proteotoxic stress.
  • In TNBC patient tumors, DYRK2 levels positively correlate with active HSF1 and are associated with poor prognosis.

Conclusions:

  • DYRK2 is a key upstream regulator of the HSF1 transcriptional program in TNBC.
  • DYRK2 promotes TNBC progression and chemoresistance by modulating HSF1 activity.
  • DYRK2 represents a potential therapeutic target for triple-negative breast cancer.

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