The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

TY - JOUR

T1 - The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

AU - Yan, Ming

AU - Gingras, Marie Claude

AU - Dunlop, Elaine A.

AU - Nouët, Yann

AU - Dupuy, Fanny

AU - Jalali, Zahra

AU - Possik, Elite

AU - Coull, Barry J.

AU - Kharitidi, Dmitri

AU - Dydensborg, Anders Bondo

AU - Faubert, Brandon

AU - Kamps, Miriam

AU - Sabourin, Sylvie

AU - Preston, Rachael S.

AU - Davies, David Mark

AU - Roughead, Taren

AU - Chotard, Laëtitia

AU - Van Steensel, Maurice A. M.

AU - Jones, Russell

AU - Tee, Andrew R.

AU - Pause, Arnim

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84902201289

U2 - 10.1172/JCI71749

DO - 10.1172/JCI71749

M3 - Article

C2 - 24762438

AN - SCOPUS:84902201289

SN - 0021-9738

VL - 124

SP - 2640

EP - 2650

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

ER -