Fumarate hydratase (FH) is a mitochondrial enzyme which is involved in aerobic cellular respiration. As discussed in a previous post, germline mutations of FH can lead to Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC), an autosomal dominant disorder which shares some phenotypic similarities with BHD syndrome. HLRCC is associated with the development of type 2 papillary kidney tumours, which is thought to involve the dysregulation of HIF signalling through a VHL-dependent mechanism (Isaacs et al., 2005). However, a recent paper by Sudarshan et al. (2011) has now linked FH expression to sporadic clear cell renal cell carcinoma (ccRCC) and HIF signalling independently of VHL.
In this study, reduced FH protein expression was seen in ccRCC tumour samples and cell lines, and reduced FH mRNA was seen in ccRCC tumours. Furthermore, siRNA-mediated knock-down of FH in two VHL-null ccRCC cell lines (786-O and A498) led to an increase in HIF2α protein levels when compared to that of FH-positive controls. Accordingly, transient and stable overexpression of FH in 786-O cells led to reduced levels of HIF2α protein, but not of HIF2α mRNA. These results suggest that FH also modulates HIF2α protein stability independently of VHL.
Sudarshan et al. then investigated the possible mechanisms behind this process. They saw that siRNA-mediated knock-down of FH led to increased AKT phosphorylation in the 786-O and A498 cell lines, and that overexpression of FH in 786-O cells reduced phospho-AKT levels. Additionally, they saw that treatment of 786-O cells with a PI3K inhibitor, in combination with the siRNA-mediated knock-down of FH, did not increase HIF2α protein levels. Consequently, it was suggested that FH may also mediate HIF2α protein expression through the PI3K/AKT signalling pathway.
Since FH-null tumours are usually highly invasive, the authors finally looked at the role FH plays in cellular migration and invasion in ccRCC. They saw that 786-O cells overexpressing FH were less motile in a wound healing assay, less migratory in a chamber assay and less invasive in a matrigel invasion assay when compared to controls. Therefore, they suggested that FH expression modulates motility, migration and invasion in ccRCC cells.
This study, as well as that by Purdue et al. (2011), adds to the growing body of work showing that HIF2α expression is important in the development and progression of renal cancer. As discussed previously, FH and FLCN are associated with HIF signalling and cellular metabolism – consequently, could FLCN also play a role in the modulation of HIF2α expression and the development of ccRCC? Answering such questions will help find new therapeutic targets for kidney cancer, as well as reliable biomarkers for more accurate disease diagnosis and prognosis.
- Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L (2005). HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. Aug; 8(2): 143-53. PMID: 16098467
- Purdue MP et al. (2011) Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat Genet. Jan; 43(1): 60-5. PMID: 21131975
- Sudarshan S, Shanmugasundaram K, Naylor SL, Lin S, Livi CB, O’Neill CF, Parekh DJ, Yeh IT, Sun LZ, Block K (2011). Reduced Expression of Fumarate Hydratase in Clear Cell Renal Cancer Mediates HIF-2α Accumulation and Promotes Migration and Invasion. PLoS One. 6(6): e21037. PMID: 21695080
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.