β-Catenin Links von Hippel-Lindau to AuroraKinase A and Loss of Primary Cilia in Renal Cell Carcinoma

von Hippel-Lindau (VHL) gene mutations are associated with clear cell renal cell carcinoma (ccRCC). A hallmark of ccRCC is loss of the primary cilium. Loss of this key organelle in ccRCC is caused by loss of VHL and associated with increased Aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) activities, which drive disassembly of the primary cilium. However, the underlying mechanism by which VHL loss increases AURKA levels has not been clearly elucidated, although it has been suggested that hypoxia-inducible factor-1 alpha (HIF-1 alpha) mediates increased AURKA expression in VHL-null cells. By contrast, we found that elevated AURKA expression is not increased by HIF-1 alpha, suggesting an alternate mechanism for AURKA dysregulation in VHL-null cells. We report here that AURKA expression is driven by beta-catenin transcription in VHL-null cells. In a panel of RCC cell lines, we observed nuclear accumulation of beta-catenin and increased AURKA signaling to HDAC6. Moreover, HIF-1 alpha inhibited AURKA expression by inhibiting beta-catenin transcription. VHL knockdown activated beta-catenin and elevated AURKA expression, decreased primary cilia formation, and caused significant shortening of cilia length in cells that did form cilia. The beta-catenin responsive transcription inhibitor iCRT14 reduced AURKA levels and rescued ciliary defects, inducing a significant increase in primary cilia formation in VHL-deficient cells. These data define a role for beta-catenin in regulating AURKA and formation of primary cilia in the setting of VHL deficiency, opening new avenues for treatment with beta-catenin inhibitors to rescue ciliogenesis in ccRCC.