E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1
Authors: Gang Xiang
Huimin Li
Hui Cong
Dan Zhao
Wei Zhang
Xiaojing Ma
Yiyi Liang
Min Du
Jian Gao
Ming Yao
Yu Gan
Hong Tu
Jin Li
Mengge Li
Yuan Fang
Journal: Frontiers in Oncology (2021)
Discipline: CLINICAL MEDICINE
Keywords: CAPZA1; UBR5; metastasis; pancreatic cancer; ubiquitination.
Affiliations: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China., Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, China., State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Abstract:  The ubiquitin-proteasome system (UPS) is a regulated mechanism of intracellular protein degradation and turnover, and its dysfunction is associated with various diseases including cancer. UBR5, an E3 ubiquitin ligase, is emerging as an important regulator of the UPS in cancers, but its role in pancreatic cancer is poorly understood. Here, we show that UBR5 is significantly upregulated in pancreatic cancer tissues. High UBR5 expression is correlated with increased lymph node metastasis and poor survival of patients. The loss-of-function and gain-of-function studies demonstrated that UBR5 substantially enhanced the in vitro migratory and invasive ability of pancreatic cancer cells. UBR5 knockdown also markedly inhibited in vivo cancer metastasis in the liver metastatic model of pancreatic cancer in nude mice, suggesting UBR5 as a potent metastatic promoter in pancreatic cancer. Furthermore, using co-immunoprecipitation combined with mass spectrometry analyses, CAPZA1, a member of F-actin capping protein α subunit family, was identified as a novel substrate of UBR5. UBR5 overexpression could promote the degradation of CAPZA1 via the UPS and induce the accumulation of F-actin, which has been described as an essential molecular event during the process of CAPZA1 deficiency-induced cancer cells migration and invasion. UBR5 knockdown significantly increased the intracellular level of CAPZA1 and CAPZA1 downregulation largely reversed the UBR5 knockdown-induced suppression of cell migration and invasion in pancreatic cancer cells. Collectively, our findings unveil UBR5 as a novel and critical regulator of pancreatic cancer metastasis and highlight the potential for UBR5-CAPZA1 axis as a therapeutic target for preventing metastasis in pancreatic cancer patients, especially in those with increased UBR5 expression. 

Retracted: No

PubPeer comments:
 This article may not be in compliance with the publisher s data availability policy since RNA sequencing data are not shared.  JEV expects that data supporting the results in the paper will be archived in an appropriate public repository. Authors are required to provide a data availability statement to describe the availability or the absence of shared data. It is said that all data were deposited with a database  EVTRACK but that database is not a sequencing data repository. Wondering if the authors could deposit the data with SRA. ,