Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers
Xuehui Hong,
He Huang,
Xingfeng Qiu,
Zhijie Ding,
Xing Feng,
Yuekun Zhu,
Huiqin Zhuo,
Jingjing Hou,
Jiabao Zhao,
Wangyu Cai,
Ruihua Sha,
Xinya Hong,
Yongxiang Li,
Hongjiang Song,
Zhiyong Zhang
Affiliations
Xuehui Hong
Longju Medical Research Center, Key Laboratory of Basic Pharmacology, Ministry of Education, Zunyi Medical College, Zunyi, China; Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
He Huang
Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China; Digestive Cancer Laboratory, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
Xingfeng Qiu
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
Zhijie Ding
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
Xing Feng
Department of Radiation Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, United States
Yuekun Zhu
Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
Huiqin Zhuo
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
Jingjing Hou
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
Jiabao Zhao
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
Wangyu Cai
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China; Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
Ruihua Sha
Department of Digestive Disease, Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, China
Xinya Hong
Department of Medical Imaging and Ultrasound, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
Yongxiang Li
Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
Hongjiang Song
Department of General Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, China
Longju Medical Research Center, Key Laboratory of Basic Pharmacology, Ministry of Education, Zunyi Medical College, Zunyi, China; Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, The State University of New Jersey, New Brunswick, United States
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.
