title: β-catenin links von Hippel-Lindau to aurora kinase A and loss of primary cilia in renal cell carcinoma.
abstract: 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-1α (HIF-1α) mediates increased AURKA expression in VHL-null cells. By contrast, we found that elevated AURKA expression is not increased by HIF-1α, suggesting an alternate mechanism for AURKA dysregulation in VHL-null cells. We report here that AURKA expression is driven by β-catenin transcription in VHL-null cells. In a panel of RCC cell lines, we observed nuclear accumulation of β-catenin and increased AURKA signaling to HDAC6. Moreover, HIF-1α inhibited AURKA expression by inhibiting β-catenin transcription. VHL knockdown activated β-catenin and elevated AURKA expression, decreased primary cilia formation, and caused significant shortening of cilia length in cells that did form cilia. The β-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 β-catenin in regulating AURKA and formation of primary cilia in the setting of VHL deficiency, opening new avenues for treatment with β-catenin inhibitors to rescue ciliogenesis in ccRCC.
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and.
authors.forename: Ruhee
authors.initials: R
authors.lastname: Dere
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and.
authors.forename: Ashley Lyn
authors.initials: AL
authors.lastname: Perkins
authors.affiliation: Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Bawa-Khalfe
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and.
authors.forename: Darius
authors.initials: D
authors.lastname: Jonasch
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and cwalker@ibt.tamhsc.edu.
authors.forename: Cheryl Lyn
authors.initials: CL
authors.lastname: Walker
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002923:Cilia / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: cell signaling; kidney cancer; renal cell biology