Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers
- Zunyi Medical College, China
- Xiangya School of Medicine, China
- Zhongshan Hospital of Xiamen University, China
- Rutgers University, United States
- The First Affiliated Hospital of Harbin Medical University, China
- Hongqi Hospital, Mudanjiang Medical University, China
- The First Affiliated Hospital of Anhui Medical University, China
- The Third Affiliated Hospital of Harbin Medical University, China
Abstract
RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development.
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Funding
National Natural Science Foundation of China (81602149)
- Xuehui Hong
Natural Science Foundation of Fujian Province (2016J01619)
- Xuehui Hong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed in accordance with NIH guidelines for the use of experimental animals. Male nonobese/severe combined immunodeficiency (NOD/SCID) mice between 4 and 6 weeks of age, obtained from the Experimental Animal Center of Shanghai Institute for Biological Sciences (SIBS). All animal work was conducted according to Institutional Animal Care Guidelines, and all animal experiments were approved by the ethical committee of the Harbin Medical University (Protocol Number: 20150619).
Human subjects: All human materials were obtained with informed consent and approved by the ethics committee of Hospital of Harbin Medical University (Protocol Number: 20150526).
Copyright
© 2018, Hong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers
eLife 7:e29511.
https://doi.org/10.7554/eLife.29511
