Abstract
Dysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.
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Acknowledgements
This work was supported by grants from The National Natural Science Foundation of China (81072047 and 81302079) and Science and Technology Planning Project of Guangdong Province, China (2016A030303005 and 2019A030317005). The authors thank Professor Jie Chen and Chang-hua Zhang (the First Affiliated Hospital of Sun Yat-sen University) for providing GC cells MGC803, MKN45, MKN28, and normal gastric epithelial cells GES-1. The authors also thank Run-jun He (the First Affiliated Hospital of Sun Yat-sen University) for providing technical assistance in flow cytometry.
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Li, GM., Li, L., Li, MQ. et al. DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy. Cell Death Differ 28, 952–967 (2021). https://doi.org/10.1038/s41418-020-00627-5
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DOI: https://doi.org/10.1038/s41418-020-00627-5
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