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

Shanshan He, Zhen Zhao, Yongfei Yang, Douglas O'Connell, Xiaowei Zhang, Soohwan Oh, Binyun Ma, Joo Hyung Lee, Tian Zhang, Bino Varghese, Janae Yip, Sara Dolatshahi Pirooz, Ming Li, Yong Zhang, Guo Min Li, Sue Ellen Martin, Keigo Machida, Chengyu Liang

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25 Scopus citations

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.

Original languageEnglish (US)
Article number8839
JournalNature communications
Volume6
DOIs
StatePublished - Aug 3 2015

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

He, S., Zhao, Z., Yang, Y., O'Connell, D., Zhang, X., Oh, S., Ma, B., Lee, J. H., Zhang, T., Varghese, B., Yip, J., Dolatshahi Pirooz, S., Li, M., Zhang, Y., Li, G. M., Ellen Martin, S., Machida, K., & Liang, C. (2015). Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. Nature communications, 6, [8839]. https://doi.org/10.1038/ncomms8839