Aurora a Overexpression and pVHL Reduced Expression Are Correlated with a Bad Kidney Cancer Prognosis

Ferchichi, Imen; Kourda, Nadia; Sassi, Samia; Romdhane, Khaled Ben; Balatgi, Sarra; Cremet, Jean Yves; Prigent, Claude; Elgaaïed, Amel Benammar

doi:10.1155/2012/804708

Cited by 9 publications

(7 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data establishing AURKA as a target for VHL ubiquitination identifies a VHL–AURKA–HDAC6 axis, and provides a mechanism whereby increased AURKA in VHL-deficient cells destabilizes axonemal microtubules of the primary cilium. Importantly, several studies have reported increased AURKA expression in RCC 20, 39 and a corresponding lack of primary cilia. 25, 40, 41 …”

Section: Discussionmentioning

confidence: 99%

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

et al. 2017

View full text Add to dashboard Cite

The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Activation of HDAC6, a tubulin deacetylase, causes disassembly of the microtubule axoneme of the primary cilia. 20 In the context of RCC, AURKA levels are elevated in ccRCC 21,22 and in high-grade renal tumors. 23 In another report, AURKA was suggested to be a specific target of HIF-1a in the setting of VHL deficiency, 24 although the exact mechanism linking HIF-1a and AURKA activation was not explored.…”

mentioning

confidence: 99%

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

Dere

Perkins

Bawa-Khalfe

et al. 2015

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

ABSTRACTvon 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 hypoxiainducible factor-1a (HIF-1a) mediates increased AURKA expression in VHL-null cells. By contrast, we found that elevated AURKA expression is not increased by HIF-1a, suggesting an alternate mechanism for AURKA dysregulation in VHL-null cells. We report here that AURKA expression is driven by b-catenin transcription in VHL-null cells. In a panel of RCC cell lines, we observed nuclear accumulation of b-catenin and increased AURKA signaling to HDAC6. Moreover, HIF-1a inhibited AURKA expression by inhibiting b-catenin transcription. VHL knockdown activated b-catenin and elevated AURKA expression, decreased primary cilia formation, and caused significant shortening of cilia length in cells that did form cilia. The b-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 b-catenin in regulating AURKA and formation of primary cilia in the setting of VHL deficiency, opening new avenues for treatment with b-catenin inhibitors to rescue ciliogenesis in ccRCC.

show abstract

“…In addition to HIF-α, pVHL interacts with certain other proteins and has multiple functions, including in microtubule dynamics, cell proliferation and growth, neuronal apoptosis, extracellular matrix deposition, DNA damage response/repair and cilia maintenance. It has been extensively reported in human cancers that loss of VHL is a predictive biomarker for the efficacy of neoadjuvant therapy (19,20). In the present study, we proposed the potential of VHL to be a predictive marker of response to AURKA inhibitors and tested our hypothesis in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 84%

VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells

et al. 2018

View full text Add to dashboard Cite

The majority of molecular targets of anticancer agents are limited to a subset of patients, and therefore identification of more specific biomarkers that can be used to improve clinical outcomes is of increasing interest. The present study showed that von Hippel‑Lindau tumor suppressor (VHL) tumor‑suppressor activity may influence the therapeutic response to Aurora kinase A (AURKA) inhibitors in human renal cell carcinoma (RCC). VHL protein (pVHL) expression was evaluated by immunoblotting in the human RCC cell lines CAKI, ACHN, 786‑O, 769‑P and A498. The anti‑tumor activities of alisertib, an AURKA‑specific chemical inhibitor, were detected by Cell Counting Kit‑8 assay in vitro and mouse xenograft model in vivo. Additionally, the VHL‑mediated anti‑tumor activity was assessed in 769‑P and CAKI cells via the loss or gain of VHL. The results revealed that VHL‑deficient 786‑O, 769‑P and A498 cells were sensitive to alisertib. By contrast, alisertib‑resistant CAKI and ACHN cells expressed the wild type VHL gene. In addition, rescue or knockdown of VHL was observed to increase or decrease alisertib anti‑proliferation activity, respectively, in RCC cells. The inverse correlation between the VHL gene expression profile and alisertib sensitivity was further confirmed in human cancer xenografts models. Taken together, these results suggested that VHL loss could potentially serve as a biomarker for predicting the efficacy of AURKA inhibitors.

show abstract

Aurora a Overexpression and pVHL Reduced Expression Are Correlated with a Bad Kidney Cancer Prognosis

Cited by 9 publications

References 42 publications

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

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

VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells

Contact Info

Product

Resources

About