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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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

Fingerprint

Autophagy
mutations
genes
Microsatellite Repeats
Colorectal Neoplasms
Genes
cancer
Mutation
Chemotherapy
Microsatellite Instability
Tumors
Neoplasms
Repair
Chemical activation
microsatellites
Defects
DNA
Epithelial-Mesenchymal Transition
DNA Repair
suppressors

ASJC Scopus subject areas

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

Cite this

Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. / He, Shanshan; Zhao, Zhen; Yang, Yongfei; O'Connell, Douglas; Zhang, Xiaowei; Oh, Soohwan; Ma, Binyun; Lee, Joo Hyung; Zhang, Tian; Varghese, Bino; Yip, Janae; Dolatshahi Pirooz, Sara; Li, Ming; Zhang, Yong; Li, Guo Min; Ellen Martin, Sue; Machida, Keigo; Liang, Chengyu.

In: Nature Communications, Vol. 6, 8839, 03.08.2015.

Research output: Contribution to journalArticle

He, S, Zhao, Z, Yang, Y, O'Connell, D, Zhang, X, Oh, S, Ma, B, Lee, JH, Zhang, T, Varghese, B, Yip, J, Dolatshahi Pirooz, S, Li, M, Zhang, Y, Li, GM, 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, vol. 6, 8839. https://doi.org/10.1038/ncomms8839
He, Shanshan ; Zhao, Zhen ; Yang, Yongfei ; O'Connell, Douglas ; Zhang, Xiaowei ; Oh, Soohwan ; Ma, Binyun ; Lee, Joo Hyung ; Zhang, Tian ; Varghese, Bino ; Yip, Janae ; Dolatshahi Pirooz, Sara ; Li, Ming ; Zhang, Yong ; Li, Guo Min ; Ellen Martin, Sue ; Machida, Keigo ; Liang, Chengyu. / Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. In: Nature Communications. 2015 ; Vol. 6.
@article{618c44c73fbf425492ae71cbd13c4368,
title = "Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers",
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.",
author = "Shanshan He and Zhen Zhao and Yongfei Yang and Douglas O'Connell and Xiaowei Zhang and Soohwan Oh and Binyun Ma and Lee, {Joo Hyung} and Tian Zhang and Bino Varghese and Janae Yip and {Dolatshahi Pirooz}, Sara and Ming Li and Yong Zhang and Li, {Guo Min} and {Ellen Martin}, Sue and Keigo Machida and Chengyu Liang",
year = "2015",
month = "8",
day = "3",
doi = "10.1038/ncomms8839",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers

AU - He, Shanshan

AU - Zhao, Zhen

AU - Yang, Yongfei

AU - O'Connell, Douglas

AU - Zhang, Xiaowei

AU - Oh, Soohwan

AU - Ma, Binyun

AU - Lee, Joo Hyung

AU - Zhang, Tian

AU - Varghese, Bino

AU - Yip, Janae

AU - Dolatshahi Pirooz, Sara

AU - Li, Ming

AU - Zhang, Yong

AU - Li, Guo Min

AU - Ellen Martin, Sue

AU - Machida, Keigo

AU - Liang, Chengyu

PY - 2015/8/3

Y1 - 2015/8/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84938509534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938509534&partnerID=8YFLogxK

U2 - 10.1038/ncomms8839

DO - 10.1038/ncomms8839

M3 - Article

C2 - 26234763

AN - SCOPUS:84938509534

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 8839

ER -