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, Steven H. Lin

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Article number4363
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Li, N., Wang, Y., Neri, S., Zhen, Y., Fong, L. W. R., Qiao, Y., Li, X., Chen, Z., Stephan, C., Deng, W., Ye, R., Jiang, W., Zhang, S., Yu, Y., Hung, M. C., Chen, J., & Lin, S. H. (2019). Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling. Nature communications, 10(1), [4363]. https://doi.org/10.1038/s41467-019-12377-1