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.
Highlights
90% of solid tumours and 75% of hematopoietic cancers exhibit some degree of aneuploidy [1]
To test whether in a similar way dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates and activates heat shock factor 1 (HSF1) in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 were increased (Fig. 1A)
The kinase activity of DYRK2 was required for the increased levels of pS326- and pS320HSF1, as a kinase-dead version of DYRK2 (DYRK2-KD) did not induce HSF1 phosphorylation
Summary
90% of solid tumours and 75% of hematopoietic cancers exhibit some degree of aneuploidy [1]. Overexpression of heat shock factor 1 (HSF1), the master regulator of the proteotoxic stress response, attenuates the negative effects of extra chromosomes on protein folding [6]. This agrees with the established critical role that HSF1 plays in tumour initiation [8] and in promoting and maintaining cancer cell proliferation [8, 9]. We report that DYRK2 phosphorylates HSF1 increasing its nuclear stability and supporting its transcriptional activity, and promoting resistance to proteotoxic stress. We further show that in clinical TNBC samples DYRK2 protein levels correlate with active HSF1, and are associated with high rates of tumour recurrence and poorer patient survival. Inhibition of DYRK2 may represent a novel approach to compromise cellular proteostasis and increase the therapeutic options for TNBC
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