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.

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Published in Nature Communications, v. 6, article 7839, p. 1-14.

© 2015 Macmillan Publishers Limited. All rights reserved.

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This work was supported by the Margaret Early Trustee Foundation, American Cancer Society (RSG-11-121-01-CCG), and NIH grant R01 CA140964 to C. Liang.

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Supplementary Figures 1-10, Supplementary Table 1 and Supplementary Reference