Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer.

Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) play an important role in the metastasis and chemoresistance in the context of colorectal cancer (CRC). Downregulation of death associated protein kinase 1 (DAPK1) may promote metastasis and chemoresistance of cancer cells through various mechanisms. However, the association between DAPK1 and CSCs or EMT has not been explored. In this study, we demonstrated that DAPK1 was associated with elevated stemness of CSCs in patients with CRC. Silencing of DAPK1 in CRC cell lines promoted the metastasis and chemoresistance due to increased stemness of CSCs and enhanced mesenchymal phenotype, an effect that was mediated via activation of the transcription factor, zinc finger E-box binding homeobox 1 (ZEB1). Blockade of this signaling pathway attenuated the stemness of CSCs and rescued the EMT process. DAPK1-ZEB1 may lie at the interface of TGF-β and WNT pathways and participate in both CSCs and EMT process. Targeted therapies aimed at DAPK1-ZEB1 pathway may inhibit the chemoresistance and metastasis of CRC. KEY MESSAGES: Downregulation of DAPK1 promotes chemoresistance and metastasis of CRC. Inhibition of DAPK1 promotes the stemness of cancer stem cells and EMT process. DAPK1-ZEB1 may lie at the interface of TGF-β and WNT pathways. DAPK1-ZEB1 participates in both CSCs and EMT process.