Using a RCC cell line derived from a BHD patient (UOK257), Preston et al. (2010) demonstrated that Folliculin also influences hypoxia-inducible factor (HIF) signalling. This pathway regulates a number of different genes that are involved in angiogenesis, erythropoiesis, cell survival and metastasis. The authors suggested that a high level of HIF-mediated expression in these FLCN-null cells alters cell metabolism through elevated levels of metabolic enzymes. This altered metabolic state parallels a phenomenon known as the Warburg effect, which is commonly seen in cancerous cells (Warburg, 1956). Warburg also postulated that cancer should in fact be interpreted as a mitochondrial disease, and further work by Klomp et al. (2010) suggests that the loss of FLCN in BHD syndrome results in mitochondrial dysfunction, as indicated by a high level of mitochondrial gene expression.
