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

• DOI: 10.1038/s41467-019-12377-1
• Publication Date: 2019-09-25T10:03:27Z
• Authors: 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; Steven H. Lin
• Keywords: AMP-Activated Protein Kinase

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