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Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells

Oncogene volume 36, pages 6738–6746 (2017)Cite this article

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Abstract

The endoplasmic reticulum (ER) stress occurs frequently in cancers. The unfolded protein response (UPR) is activated to cope with ER stress. This has generated widespread interest in targeting UPR as therapeutic strategies. Inositol-requiring transmembrane kinase/endonuclease 1α (IRE1α), an ER stress sensor, is a key component of UPR. However, the role of IRE1α in tumorigenesis remains unclear. The purpose of this work is to investigate the role of IRE1α in colon cancer and to determine whether IRE1α could serve as a target for therapy. We found that knockdown of IRE1α suppressed the proliferation of colon cancer cells in vitro and xenograft growth in vivo. Inhibition of expression of IRE1α decreased stemness of colon cancer stem cells (CSCs) and attenuated growth of intestinal organoids. Genetic ablation of IRE1α prevented the colitis-associated colonic tumorigenesis in mice. The mechanistic study indicates that knockdown of IRE1α repressed the expression of β-catenin, a key factor that drives colonic tumorigenesis, through activating pancreatic ER kinase/eukaryotic translation initiation factor 2α signaling. We found that the IRE1a-specific inhibitor 4μ8C could suppress the production of β-catenin, inhibited the proliferation of colon cancer cells, repressed colon CSCs and prevented xenograft growth. The results suggest that IRE1α has a critical role in colonic tumorigenesis and IRE1α targeting might be a strategy for treatment of colon cancers.

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Acknowledgements

This work was funded by STCSM (16JC1406100), NSFC (31270829, 31470769, 31670785), Chinese Academy of Sciences (XDA08030300, KFJ-EW-STS-099) and CAS/SAFEA International Partnership Program for Creative Research Teams. We thank Dr Xie for kindly providing the vectors.

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Authors and Affiliations

  1. Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    X-X Li, H-S Zhang, Y-M Xu, R-J Zhang, Y Chen, L Fan, Y-Q Qin & J Fang

  2. College of Life Sciences Wuhan University, Wuhan, China

    Y Liu

  3. University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    M Li

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  1. X-X Li
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Correspondence to J Fang.

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Li, XX., Zhang, HS., Xu, YM. et al. Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells. Oncogene 36, 6738–6746 (2017). https://doi.org/10.1038/onc.2017.284

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