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

doi:10.1038/s41467-019-12377-1

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

Nat Commun. 2019 Sep 25;10(1):4363. doi: 10.1038/s41467-019-12377-1.

Authors

Nan Li¹, Yifan Wang^{2

3

4}, Shinya Neri², Yuanli Zhen⁵, Lon Wolf R Fong^{3

6}, Yawei Qiao², Xu Li^{2

7}, Zhen Chen², Clifford Stephan⁸, Weiye Deng^{4

9}, Rui Ye^{2

3}, Wen Jiang^{4

9}, Shuxing Zhang⁶, Yonghao Yu⁵, Mien-Chie Hung^{3

10}, Junjie Chen^{11

12}, Steven H Lin^{13

14

15}

Affiliations

¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. nli4@mdanderson.org.
² Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
³ The University of Texas Graduate School of Biomedical Sciences Houston, Houston, TX, 77030, USA.
⁴ Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 75219, USA.
⁵ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁶ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁷ School of Life Science, Westlake University, Hangzhou, 310024, China.
⁸ Center for Translational Cancer Research, The Institute of Biosciences and Technology at Texas A&M University, Houston, TX, 77030, USA.
⁹ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁰ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. jchen8@mdanderson.org.
¹² The University of Texas Graduate School of Biomedical Sciences Houston, Houston, TX, 77030, USA. jchen8@mdanderson.org.
¹³ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. SHLin@mdanderson.org.
¹⁴ The University of Texas Graduate School of Biomedical Sciences Houston, Houston, TX, 77030, USA. SHLin@mdanderson.org.
¹⁵ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. SHLin@mdanderson.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases / antagonists & inhibitors*
AMP-Activated Protein Kinases / metabolism
Animals
Carcinogenesis / drug effects
Carcinogenesis / genetics
Cell Line, Tumor
Energy Metabolism / drug effects*
Enzyme Inhibitors / pharmacology*
HeLa Cells
Homeostasis / drug effects
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics
Sulfones / pharmacology
Tankyrases / antagonists & inhibitors*
Tankyrases / metabolism
Triazoles / pharmacology
Xenograft Model Antitumor Assays / methods
para-Aminobenzoates / pharmacology

Substances

Enzyme Inhibitors
G007-LK
JW55 compound
Sulfones
Triazoles
para-Aminobenzoates
Tankyrases
Protein Serine-Threonine Kinases
STK11 protein, human
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding