Data from Formation of Renal Cysts and Tumors in <i>Vhl/Trp53</i>-Deficient Mice Requires HIF1α and HIF2α

<div>Abstract<p>The von Hippel–Lindau (<i>VHL</i>) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of <i>Vhl</i> alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1α has been implicated as a renal tumor suppressor, whereas HIF2α is considered an oncoprotein. In this study, we investigated the contributions of HIF1α and HIF2α to ccRCC initiation in the context of <i>Vhl</i> deficiency. We found that deleting <i>Vhl</i> plus <i>Hif1a</i> or <i>Hif2a</i> specifically in the renal epithelium did not induce tumor formation. However, HIF1α and HIF2α differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in <i>Vhl</i>-deficient renal epithelial cells. HIF1α, but not HIF2α, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in <i>Vhl</i> mutant renal cells before ccRCC formation. Importantly, deletion of either <i>Hif1a</i> or <i>Hif2a</i> completely prevented the formation of renal cysts and tumors in <i>Vhl/Trp53</i> mutant mice. These findings argue that both HIF1α and HIF2α exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. <i>Cancer Res; 76(7); 2025–36. ©2016 AACR</i>.</p></div>