VHL-dependence of EHHADH Expression in a Human Renal Cell Carcinoma Cell Line

The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in up to 90% of clear cell renal cell carcinoma (ccRCC) cases, thus playing a key role in ccRCC pathogenesis. ccRCC can be classified as a metabolic disease in which alterations in fatty acid metabolism facilitate cancer cell proliferation. Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH) is an enzyme involved in peroxisomal fatty acid degradation. It is primarily expressed in renal proximal tubule cells, presumably the origin of ccRCC. Although EHHADH is still a relatively unexplored gene, it is known to be differentially expressed in several tumors. In this study, analysis of several databases revealed that EHHADH expression is downregulated in ccRCC samples compared to healthy kidney samples. Moreover, cell culture experiments were performed to investigate the relationship between EHHADH and VHL at the gene and protein level. qPCR and Western blot analyses using the human ccRCC cell line RCC4 revealed that EHHADH is expressed in a VHL-dependent manner. RCC4 cells reconstituted with VHL show significantly higher EHHADH mRNA and protein levels than VHL-deficient RCC4 control cells. These results indicate that the downregulation of EHHADH in ccRCC reported may be due to the loss of VHL function. This study is the first to molecularly characterize EHHADH, a key enzyme in peroxisomal ß-oxidation, in relation to VHL, suggesting a potential pathogenic interaction that is worthy of further investigation

SCD5 Regulation by VHL Affects Cell Proliferation and Lipid Homeostasis in ccRCC

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer, and inactivation of the VHL tumor suppressor gene is found in almost all cases of hereditary and sporadic ccRCCs. CcRCC is associated with the reprogramming of fatty acid metabolism, and stearoyl-CoA desaturases (SCDs) are the main enzymes controlling fatty acid composition in cells. In this study, we report that mRNA and protein expression of the stearoyl-CoA desaturase SCD5 is downregulated in VHL-deficient cell lines. Similarly, in C. elegans vhl-1 mutants, FAT-7/SCD5 activity is repressed, supporting an evolutionary conservation. SCD5 regulation by VHL depends on HIF, and loss of SCD5 promotes cell proliferation and a metabolic shift towards ceramide production. In summary, we identify a novel regulatory function of VHL in relation to SCD5 and fatty acid metabolism, and propose a new mechanism of how loss of VHL may contribute to ccRCC tumor formation and progression

Projections of regional changes in forest net primary productivity for different tree species in Europe driven by climate change and carbon dioxide

International audience& Context Projecting changes in forest productivity in Europe is crucial for adapting forest management to chang-ing environmental conditions. & Aims The objective of this paper is to project forest pro-ductivity changes under different climate change scenarios at a large number of sites in Europe with a stand-scale process-based model. & Methods We applied the process-based forest growth mod-el 4C at 132 typical forest sites of important European tree species in ten environmental zones using climate change scenarios from three different climate models and two dif-ferent assumptions about CO 2 effects on productivity. & Results This paper shows that future forest productivity will be affected by climate change and that these effects depend strongly on the climate scenario used and the persistence of CO 2 effects. We find that productivity increases in Northern Europe, increases or decreases in Central Europe, and decreases in Southern Europe. This geographical pattern is mirrored by the responses of the individual tree species. The productivity of Scots pine and Norway spruce, mostly located in central and north-ern Europe, increases while the productivity of Common beech and oak in southern regions decreases. It is im-portant to note that we consider the physiological re-sponse to climate change excluding disturbances or management. & Conclusions Different climate change scenarios and as-sumptions about the persistence of CO 2 effects lead to un-certain projections of future forest productivity. These un-certainties need to be integrated into forest management planning and adaptation of forest management to climate change using adaptive management frameworks

Forests under climate change: potential risks and opportunities

Climate change will affect forests in Germany through the end of this century. The impacts of climate change on forest productivity, water budget and the associated biotic and abiotic risks are relevant for the forestry sector and its decision makers. We analysed the possible impacts of climate change on Germany’s forests using a variety of climate scenarios generated with the regional statistical climate model STARS and the process-based forest growth model 4C. The focus of our analyses was on mono-specific stands of the main tree species Norway spruce (Picea abies L. Karst.), Scots pine (Pinus sylvestris L.), European beech (Fagus sylvatica L.), oak (Quercus robur L. and Quercus petraea Liebl.), and Douglas fir (Pseudotsuga menziesii (Mirb.) Franco). The impacts on net primary production of forest stands are mainly positive for needle tree species and more negative at low elevation, water-limited sites for broadleaved tree species like beech, which is in contrast to the overall tendency of deterioration of the annual percolation rates independent of tree species. The application of a fire danger index and a nun moth risk species index according to Zwölfer indicates that Germany’s forests will experience, under the warmer and dryer climate described by RCP8.5, higher potential risks from fire and some specific pest species. An integrated evaluation reflecting the potentials and risks of forests under RCP8.5 for the German natural regions illustrates that the dryer (water-limited) low elevated regions reaching from southwestern to northeastern Germany will benefit less from the assumed climate change than regions in the Northwest and forest sites at higher altitudes, which are mainly temperature limited