Now we’ve been introduced, I thought I’d draw your attention to a recently published paper that has confirmed and expanded our understanding of the pathogenic mechanisms underlying BHD syndrome.
As Duncan mentioned in earlier posts, BHD syndrome shares some phenotypic similarities with other rare diseases, such as HLRCC, TSC and VHL disease. Hypoxia-inducible factor (HIF) controls processes such as cell proliferation and cell metabolism under conditions of reduced tissue oxygenation and has been implicated in tumour growth within all these disorders. Recent work published in Oncogene by Preston et al. has now suggested that HIF has a role to play in BHD syndrome.
Using the FLCN null cell line UOK257, Preston et al. demonstrated increased levels of HIF1α and HIF2α-mediated gene expression under both normoxic and hypoxic conditions. The protein levels of various HIF targets were also increased in cells lacking FLCN. This increase in HIF-mediated expression after loss of FLCN does not result from elevated levels of HIF1α or HIF2α, but rather an increase in their activity.
FLCN is known to have an involvement in the AMPK signalling pathway, which is a recognised modulator of HIF. Therefore FLCN null cells could potentially activate HIF through a dysregulation of AMPK. Other signalling pathways which activate HIF include the Akt and mTOR pathways, which again have a FLCN connection. While the finer details still need investigating, it goes without saying that the role FLCN plays in all these different pathways is complex, and that they must not be thought of in isolation. What this paper and that of Hong et al. emphasise is that Folliculin is not just associated with mTOR/AMPK signalling, but it is involved in a dense signalling network.
Additionally, the data presented by Preston et al. suggest that a high level of HIF-mediated expression in FLCN null cells alters cell metabolism through elevated levels of metabolic enzymes. This altered metabolic state parallels a phenomenon known as the Warburg effect, commonly seen in cancerous cells and also described in HLRCC tumours (Sudarshan et al., 2007). I will talk about this in more detail very soon as it’s interesting from both a historical and scientific standpoint, and furthermore it could open up a new area of potential therapies for BHD syndrome.
- Hong SB et al. Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol Cancer. 2010 Jun 23;9(1):160.
- Preston RS et al. 2010. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene. Nov 8 (Epublication ahead of print).
- Sudarshan S et al. 2007. HIF and fumarate hydratase in renal cancer. Br J Cancer. 96(3): 403–407
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.