CDK5/FBW7-dependent Ubiquitination and Degradation of EZH2 Inhibits Pancreatic Cancer Cell Migration and Invasion [Protein Synthesis and Degradation]

Pancreatic cancer is one of the most lethal cancer types. Enhancer of zeste homolog 2 (EZH2) is an oncogenic protein and overexpressed in pancreatic cancer, and EZH2 could be a potential therapeutic target for the treatment of pancreatic cancer. Although significant progress has been made toward understanding the function and deregulation of EZH2 in cancer cells, the post-translational regulation of EZH2 in cancer cells is still unclear. F-box and WD repeat domain-containing 7 (FBW7) acts as a tumor suppressor by targeting multiple oncoprotein substrates for ubiquitination and degradation. Here, we demonstrated that EZH2 was a bona fide substrate of FBW7 in pancreatic cancer cells. We provided evidence that the activated CDK5 kinase was involved in the EZH2 phosphorylation that was required for FBW7-mediated degradation. We further showed that FBW7 suppressed EZH2 activity and inhibited tumor migration and invasion via degradation of EZH2 in pancreatic cancer cells. Furthermore, immunohistochemistry analysis revealed that expression of EZH2 protein negatively correlated with FBW7 protein levels in a cohort of human pancreatic cancer specimens. Collectively, our findings demonstrate FBW7 as a novel E3 ligase of EZH2 regulates of EZH2 protein level in pancreatic cancer and represents a viable strategy for effective treatment of pancreatic cancer.

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