The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

Yan, Ming and Gingras, Marie Claude and Dunlop, Elaine A. and Nouët, Yann and Dupuy, Fanny and Jalali, Zahra and Possik, Elite and Coull, Barry J. and Kharitidi, Dmitri and Dydensborg, Anders Bondo and Faubert, Brandon and Kamps, Miriam and Sabourin, Sylvie and Preston, Rachael S. and Davies, David Mark and Roughead, Taren and Chotard, Laëtitia and Van Steensel, Maurice A.M. and Jones, Russell and Tee, Andrew R. and Pause, Arnim (2014) The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. Journal of Clinical Investigation, 124 (6). pp. 2640-2650. ISSN 0021-9738

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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.

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Journal Article
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Journal of Clinical Investigation
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21 Aug 2019 13:51
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18 Sep 2023 01:39