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The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

Research output: Contribution to journalJournal articlepeer-review

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  • Ming Yan
  • Marie Claude Gingras
  • Elaine A. Dunlop
  • Yann Nouët
  • Fanny Dupuy
  • Zahra Jalali
  • Elite Possik
  • Dmitri Kharitidi
  • Anders Bondo Dydensborg
  • Brandon Faubert
  • Miriam Kamps
  • Sylvie Sabourin
  • Rachael S. Preston
  • David Mark Davies
  • Taren Roughead
  • Laëtitia Chotard
  • Maurice A.M. Van Steensel
  • Russell Jones
  • Andrew R. Tee
  • Arnim Pause
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<mark>Journal publication date</mark>2/06/2014
<mark>Journal</mark>Journal of Clinical Investigation
Issue number6
Volume124
Number of pages11
Pages (from-to)2640-2650
Publication StatusPublished
<mark>Original language</mark>English

Abstract

The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.