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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.

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