Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers
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.
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.
[…] All data for UVRAG frameshift mutation in human CRC, gastric, and endometrial cancers with MSI were obtained from SelTarbase (http://www.seltarbase.org/) and primary public sources. All data for DNA sequence alteration, chromosomal structure variants, and clinical information in gastric cancer were obtained from cBioportal (http://www.cbioportal.org) and primary sources. All statistical analyses were carried out using the R software package. Circos plots were carried out using Circos (http://circos.ca/). […]
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