Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation

Yapeng Ji, Chuanzhen Yang, Zefang Tang, Yongfeng Yang, Yonglu Tian, Hongwei Yao, Xi Zhu, Zemin Zhang, Jiafu Ji and Xiaofeng Zheng ()
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Yapeng Ji: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University
Chuanzhen Yang: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University
Zefang Tang: Biodynamic Optical Imaging Center, School of Life Sciences, Peking University
Yongfeng Yang: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University
Yonglu Tian: School of Life Sciences, Peking University
Hongwei Yao: The Third Hospital, Peking University
Xi Zhu: The Third Hospital, Peking University
Zemin Zhang: Biodynamic Optical Imaging Center, School of Life Sciences, Peking University
Jiafu Ji: Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute
Xiaofeng Zheng: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Targeting the specific metabolic phenotypes of colorectal cancer stem cells (CRCSCs) is an innovative therapeutic strategy for colorectal cancer (CRC) patients with poor prognosis and relapse. However, the context-dependent metabolic traits of CRCSCs remain poorly elucidated. Here we report that adenylate kinase hCINAP is overexpressed in CRC tissues. Depletion of hCINAP inhibits invasion, self-renewal, tumorigenesis and chemoresistance of CRCSCs with a loss of mesenchymal signature. Mechanistically, hCINAP binds to the C-terminal domain of LDHA, the key regulator of glycolysis, and depends on its adenylate kinase activity to promote LDHA phosphorylation at tyrosine 10, resulting in the hyperactive Warburg effect and the lower cellular ROS level and conferring metabolic advantage to CRCSC invasion. Moreover, hCINAP expression is positively correlated with the level of Y10-phosphorylated LDHA in CRC patients. This study identifies hCINAP as a potent modulator of metabolic reprogramming in CRCSCs and a promising drug target for CRC invasion and metastasis.

Date: 2017
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DOI: 10.1038/ncomms15308

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