DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress in triplenegative breast cancer

SummaryTo survive aneuploidy-induced proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive target. As developing HSF1 inhibitors is challenging, the identification and targeting of upstream regulators of HSF1 presents 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. Thus, 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. In agreement with this, DYRK2 depletion reduces tumour growth in a TNBC xenograft model. These findings identify DYRK2 as both, a key modulator of the HSF1 transcriptional program, and a potential therapeutic target.

Download Full-text

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

Cell Death and Differentiation ◽

10.1038/s41418-020-00686-8 ◽

2020 ◽

Author(s):

Rita Moreno ◽

Sourav Banerjee ◽

Angus W. Jackson ◽

Jean Quinn ◽

Gregg Baillie ◽

...

Keyword(s):

Heat Shock ◽

Cancer Progression ◽

Therapeutic Target ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Proteotoxic Stress ◽

Dual Specificity ◽

Stress Response Pathway ◽

Nuclear Stability ◽

Attractive Therapeutic Target

AbstractTo 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.

Download Full-text

Heat Shock Factor 1 (HSF1) as a new tethering factor for ESR1 supporting its action in breast cancer.

10.1101/2021.05.06.442900 ◽

2021 ◽

Author(s):

Natalia Vydra ◽

Patryk Janus ◽

Paweł Kuś ◽

Tomasz Stokowy ◽

Katarzyna Mrowiec ◽

...

Keyword(s):

Breast Cancer ◽

Heat Shock ◽

Heat Shock Factor ◽

Regulation Of Transcription ◽

Heat Shock Factor 1 ◽

Transcriptional Responses ◽

Proteotoxic Stress ◽

Basal Expression ◽

Mitogenic Action ◽

Er Positive

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was recently linked to estrogen (E2) signaling through ESR1. We found that an HSF1 deficiency could lead to the inhibition of the mitogenic action of E2 in breast cancer cells. The stimulatory effect of E2 on the transcriptome is weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ESR1 to chromatin. HSF1 and ESR1 can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ESR1 through a mechanism involving chromatin reorganization. Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome diversity in ER-positive breast cancer and can enhance the genomic action of ESR1. Moreover, ESR1 and HSF1 are only prognostic when analyzed together (the worst prognosis for ER−/HSF1high cancers).

Download Full-text

Regulation of Autophagy by the Heat Shock Factor 1-Mediated Stress Response Pathway

Heat Shock Proteins and Stress - Heat Shock Proteins ◽

10.1007/978-3-319-90725-3_9 ◽

2018 ◽

pp. 167-178

Author(s):

Yoshihisa Watanabe ◽

Masaki Tanaka

Keyword(s):

Stress Response ◽

Heat Shock ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Stress Response Pathway

Download Full-text

Heat shock factor 1 confers resistance to lapatinib in ERBB2-positive breast cancer cells

Cell Death and Disease ◽

10.1038/s41419-018-0691-x ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 11

Author(s):

Alisha Yallowitz ◽

Amr Ghaleb ◽

Lucas Garcia ◽

Evguenia M. Alexandrova ◽

Natalia Marchenko

Keyword(s):

Breast Cancer ◽

Heat Shock ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Positive Breast Cancer

Download Full-text

Heat Shock Factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells

eLife ◽

10.7554/elife.69843 ◽

2021 ◽

Vol 10 ◽

Author(s):

Natalia Vydra ◽

Patryk Janus ◽

Paweł Kuś ◽

Tomasz Stokowy ◽

Katarzyna Mrowiec ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Heat Shock ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Estrogen Receptor Α ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Er Positive ◽

Positive Breast Cancer

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers, an elevated HSF1 level is associated with metastatic disease.

Download Full-text