Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling

Nan Li (), Yifan Wang, Shinya Neri, Yuanli Zhen, Lon Wolf R. Fong, Yawei Qiao, Xu Li, Zhen Chen, Clifford Stephan, Weiye Deng, Rui Ye, Wen Jiang, Shuxing Zhang, Yonghao Yu, Mien-Chie Hung, Junjie Chen () and Steven H. Lin ()
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Nan Li: The University of Texas MD Anderson Cancer Center
Yifan Wang: The University of Texas MD Anderson Cancer Center
Shinya Neri: The University of Texas MD Anderson Cancer Center
Yuanli Zhen: University of Texas Southwestern Medical Center
Lon Wolf R. Fong: The University of Texas Graduate School of Biomedical Sciences Houston
Yawei Qiao: The University of Texas MD Anderson Cancer Center
Xu Li: The University of Texas MD Anderson Cancer Center
Zhen Chen: The University of Texas MD Anderson Cancer Center
Clifford Stephan: The Institute of Biosciences and Technology at Texas A&M University
Weiye Deng: University of Texas Southwestern Medical Center
Rui Ye: The University of Texas MD Anderson Cancer Center
Wen Jiang: University of Texas Southwestern Medical Center
Shuxing Zhang: The University of Texas MD Anderson Cancer Center
Yonghao Yu: University of Texas Southwestern Medical Center
Mien-Chie Hung: The University of Texas Graduate School of Biomedical Sciences Houston
Junjie Chen: The University of Texas MD Anderson Cancer Center
Steven H. Lin: The University of Texas MD Anderson Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.

Date: 2019
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DOI: 10.1038/s41467-019-12377-1

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