FLCN Regulates Metabolic Reprogramming via AMPK Signaling to HIF1α

Germline inactivating mutations in folliculin (FLCN) lead to the Birt–Hogg–Dubé (BHD) hereditary cancer predisposition syndrome. FLCN loss increases the transcriptional activity of hypoxia inducible factor (HIF) in renal cancer cells and induces a shift to aerobic glycolysis, a tumor-associated metabolic adaptation known as the Warburg effect, through unknown mechanisms. Yan and colleagues found that Flcn^−/− mouse embryonic fibroblasts (MEF) displayed elevated HIF transcriptional activity, but not protein levels, under normoxic conditions, and exhibited increased aerobic glycolysis that was dependent on HIF1α and could be rescued by FLCN. FLCN is an AMPK binding protein, and Flcn^−/−MEFs exhibited increased AMP-activated protein kinase (AMPK) activity in normoxia. Chronic AMPK activation in turn led to phosphorylation and activation of peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), a key regulator of mitochondrial biogenesis. Consistent with this finding, mitochondria were more abundant in Flcn^−/− MEFs, and levels of reactive oxygen species (ROS), a known driver of HIF activation in normoxia, were elevated due to the increased mitochondrial load. Moreover, knockdown of PGC-1α or antioxidant-mediated ROS inhibition blocked transcription of HIF target genes in Flcn^−/− MEFs, indicating that FLCN loss induces HIF activation through AMPK-mediated PGC-1 α activation, increased mitochondrial biogenesis, and ROS production. Although FLCN loss did not confer a proliferative advantage in a non-BHD syndrome FLCN-null follicular thyroid cancer cell line, FLCN deficiency enhanced HIF1α–dependent anchorage-independent growth and growth in vivo in association with increased AMPK activation, PGC-1α expression, mitochondrial biogenesis, ROS production, HIF target gene activation, and aerobic glycolysis. Additionally, increased mitochondrial abundance, HIF1α nuclear staining, and HIF target expression were observed in a chromophobe tumor from a patient with BHD, further suggesting that FLCN loss induces AMPK–HIF-dependent metabolic reprogramming that confers a tumorigenic advantage. Together, these findings indicate that FLCN exerts tumor suppressor activity in part by acting as a negative regulator of AMPK-dependent HIF activation and the Warburg effect.

Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest 2014 Apr 24 [Epub ahead of print].