title: CDK5/FBW7-dependent ubiquitination and degradation of EZH2 inhibits pancreatic cancer cell migration and invasion.
abstract: Pancreatic cancer is one of the most lethal cancer types. Enhancer of zeste homolog 2 (EZH2) is an oncogenic protein 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 posttranslational 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 demonstrate that EZH2 is abona fidesubstrate of FBW7 in pancreatic cancer cells. We provide evidence that the activated CDK5 kinase is involved in the EZH2 phosphorylation that is required for FBW7-mediated degradation. We further show that FBW7 suppresses EZH2 activity and inhibits tumor migration and invasion via degradation of EZH2 in pancreatic cancer cells. Furthermore, immunohistochemistry analysis revealed that expression of EZH2 protein negatively correlates with FBW7 protein levels in a cohort of human pancreatic cancer specimens. Collectively, our findings demonstrate that FBW7 is a novel E3 ligase of EZH2 that regulates the EZH2 protein level in pancreatic cancer and represents a viable strategy for effective treatment of pancreatic cancer.
authors.affiliation: From the Departments of Digestive Surgical Oncology and.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: the Organ Transplantation Center, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China, and.
authors.forename: Chong
authors.initials: C
authors.lastname: Yang
authors.affiliation: From the Departments of Digestive Surgical Oncology and.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: From the Departments of Digestive Surgical Oncology and.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: From the Departments of Digestive Surgical Oncology and.
authors.forename: Wanli
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Digestive Surgical Oncology and.
authors.forename: Sudong
authors.initials: S
authors.lastname: Zhan
authors.affiliation: From the Departments of Digestive Surgical Oncology and.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: the Department of Gastroenterology, Jiangxi Institute of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China wdj5257@sina.com.
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China, heshuiwu@163.com.
authors.forename: Heshui
authors.initials: H
authors.lastname: Wu
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D009363:Neoplasm Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D044767:Ubiquitin-Protein Ligases; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human
keywords: E3 ubiquitin ligase; cell invasion; cell migration; pancreatic cancer; ubiquitylation (ubiquitination)