The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation.
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.
Ming
M
Yan
Marie-Claude
MC
Gingras
Elaine A
EA
Dunlop
Yann
Y
Nouët
Fanny
F
Dupuy
Zahra
Z
Jalali
Elite
E
Possik
Barry J
BJ
Coull
Dmitri
D
Kharitidi
Anders Bondo
AB
Dydensborg
Brandon
B
Faubert
Miriam
M
Kamps
Sylvie
S
Sabourin
Rachael S
RS
Preston
David Mark
DM
Davies
Taren
T
Roughead
Laëtitia
L
Chotard
Maurice A M
MA
van Steensel
Russell
R
Jones
Andrew R
AR
Tee
Arnim
A
Pause
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D058249:Birt-Hogg-Dube Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004734:Energy Metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C526060:Bhd protein, mouse; C476078:FLCN protein, human; D051793:Hypoxia-Inducible Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases