Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers

Shanshan He, Zhen Zhao, Yongfei Yang, Douglas O'Connell, Xiaowei Zhang, Soohwan Oh, Binyun Ma, Joo-Hyung Lee, Tian Zhang, Bino Varghese, Janae Yip, Sara Dolatshahi Pirooz, Ming Li, Yong Zhang, Guo-Min Li, Sue Ellen Martin, Keigo Machida and Chengyu Liang ()
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Shanshan He: Keck Medical School, University of Southern California
Zhen Zhao: Keck Medical School, University of Southern California
Yongfei Yang: Keck Medical School, University of Southern California
Douglas O'Connell: Keck Medical School, University of Southern California
Xiaowei Zhang: Keck Medical School, University of Southern California
Soohwan Oh: Keck Medical School, University of Southern California
Binyun Ma: Keck Medical School, University of Southern California
Joo-Hyung Lee: Keck Medical School, University of Southern California
Tian Zhang: Keck Medical School, University of Southern California
Bino Varghese: Keck Medical School, University of Southern California
Janae Yip: Keck Medical School, University of Southern California
Sara Dolatshahi Pirooz: Keck Medical School, University of Southern California
Ming Li: Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute
Yong Zhang: the First Affiliated Hospital of Medical College, Xi’an Jiaotong University
Guo-Min Li: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington
Sue Ellen Martin: Keck Medical School, University of Southern California
Keigo Machida: Keck Medical School, University of Southern California
Chengyu Liang: Keck Medical School, University of Southern California

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAGFS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAGFS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAGFS can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAGFS expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.

Date: 2015
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DOI: 10.1038/ncomms8839

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