DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress and tumour growth in triple-negative breast cancer

Summary The proteotoxic-stress response pathway, controlled by heat shock factor 1 (HSF1), supports both cancer progression and chemoresistance and is an attractive target for cancer treatment. As developing HSF1 inhibitors has proved to be very challenging, the identification and targeting of upstream regulators of HSF1 presents a more tractable alternative strategy. Here we demonstrate that in triple negative breast cancer (TNBC) cells, the dual-specificity tyrosine-regulated kinase 2 (DYRK2) directly interacts with and 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 protein levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. In agreement with this, DYRK2 depletion significantly reduces tumour growth in a TNBC xenograft model. These findings identify DYRK2 as both, an important modulator of the HSF1 transcriptional program, and a potential therapeutic target in TNBC.