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.
Highlights
Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis
The overall expression of UVRAGWT was diminished in microsatellite instability (MSI) cells with the FS mutation (Fig. 1b), and the levels of UVRAGFS were inversely correlated with the expression of UVRAGWT in all tested cell lines (Fig. 1c)
The UVRAG FS mutation was present in one of the four analysed cases of human primary colorectal cancer (CRC) with MSI, but not in primary MSS CRC or in normal colorectal mucosa (Fig. 1d, Supplementary Table 1). This is in line with a previous report2a that evaluated the mutation frequencies in 137 genes in MSI cancers, revealing the high frequency of the A10 UVRAG FS mutation that was found in 33% CRC, 8% endometrial and 7.8% gastric cancers with MSI (Supplementary Fig. 1e)
Summary
Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. 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 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. Increasing evidence suggests that MMR deficiency per se is not sufficient to drive cell transformation and tumorigenesis, but that microsatellite mutations in a limited number of target genes might be positively selected during tumour development and underlie MSI-associated pathogenesis and treatment response[3,4]. Our data identified the underlying pathogenic mechanisms beyond autophagy that are associated with UVRAGFS-positive cancers and suggest that expression of UVRAGFS might be a predictive factor for chemotherapy response
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