DAPK-HSF1 interaction as a new positive feedback loop for TNF-induced apoptosis in colorectal cancer cells

Abstract

Death-associated protein kinase (DAPK) is a serine-threonine kinase with tumor suppressor function. Previously we demonstrated that TNF induced DAPK-mediated apoptosis in colorectal cancer. However the protein-protein interaction network associated with TNF-DAPK signaling still remains unclear. We identified HSF1 as a new DAPK phosphorylation target in response to low concentration of TNF and verified a physical interaction between DAPK and HSF1 both in vitro and in vivo. We show that HSF1 binds to the DAPK promoter. Transient over-expression of HSF1 protein led to an increase in DAPK mRNA level and consequently to an enforcement of apoptosis. In contrast, treatment with a DAPK specific inhibitor as well as DAPKsh knockdown abolished the activation of HSF1 at Ser230. Furthermore, translational studies demonstrated a positive correlation between DAPK and pHSF1S230 protein expression in human colorectal carcinoma tissues. Together, our data define a novel link between DAPK and HSF1 and highlight a positive feedback loop in DAPK regulation under mild inflammatory stress in colorectal tumors. For the first time we show that under TNF the pro-survival HSF1 protein can be redirected to a pro-apoptotic program.