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

Citations Over TimeTop 10% of 2015 papers

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 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.

Related Papers

• Inactivation of the p53 tumor suppressor gene and activation of the Ras oncogene: cooperative events in tumorigenesis.(2010)
• → Functional Innovation through Gene Duplication Followed by Frameshift Mutation(2022)4 cited
• → A double mutation in a patient with X-linked myotubular myopathy(2001)4 cited
• [Development of anti-cancer drugs mediated by apoptosis and autophagy].(2015)
• [Role of the tumor suppressor ARF in oncogenesis].(2009)