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

• Published in: Nature communications 2015-08, Vol.6 (1), p.7839, Article 7839
• Main Authors: He, Shanshan, Zhao, Zhen, Yang, Yongfei, O'Connell, Douglas, Zhang, Xiaowei, Oh, Soohwan, Ma, Binyun, Lee, Joo-Hyung, Zhang, Tian, Varghese, Bino, Yip, Janae, Dolatshahi Pirooz, Sara, Li, Ming, Zhang, Yong, Li, Guo-Min, Ellen Martin, Sue, Machida, Keigo, Liang, Chengyu
• Format: Article
• Language: English
• Subjects: 13; 13/106; 38; 631/80/39; 64; 692/308; 692/420/2489/144/68; 692/699/67/1504/1885; 82; 82/80; Adult; Aged; Animals; Antimetabolites, Antineoplastic - pharmacology; Autophagy; Autophagy - genetics; Cancer; Carcinogenesis - genetics; Cell Line, Tumor; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Deoxyribonucleic acid; DNA; DNA repair; DNA Repair - genetics; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Fluorouracil - pharmacology; Frameshift Mutation; Genetic Predisposition to Disease; HCT116 Cells; HEK293 Cells; HeLa Cells; HT29 Cells; Humanities and Social Sciences; Humans; Immunohistochemistry; Male; Mesenchyme; Metastases; Mice; Microsatellite Instability; Microscopy, Confocal; Middle Aged; Mouse Embryonic Stem Cells; multidisciplinary; Mutation; Neoplasm Invasiveness - genetics; Neoplasm Metastasis - genetics; Neoplasm Transplantation; NIH 3T3 Cells; Pathogenesis; Phagocytosis; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Science; Science (multidisciplinary); Stability; Tumor Burden - drug effects; Tumor Suppressor Proteins - genetics; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8839

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 UVRAG FS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG FS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG FS can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAG FS 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. Some colon carcinomas with microsatellite instability carry a frameshift mutation in a tumour suppressor UVRAG. Here the authors show that mutant UVRAG triggers colorectal cancer by antagonizing the activity of normal UVRAG in autophagy and chromosomal stability, but also sensitizes the cancer to DNA damage-inducing chemotherapeutic drugs.