VHL Inactivation Induces HEF1 and Aurora Kinase A

Xu, Jian; Li, Huapeng; Wang, Bo; Xu, Yan; Yang, Jiayin; Zhang, Xiaofei; Harten, Sarah K.; Shukla, Deepa; Maxwell, Patrick H.; Pei, Duanqing; Esteban, Miguel A.

doi:10.1681/asn.2010040345

Cited by 66 publications

(61 citation statements)

References 30 publications

(42 reference statements)

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“…First, we overexpressed a constitutively stable form of HIF-2a (HIF-2a DM) in VHL-defective CCRCC cell lines (RCC10 and RCC4; Xu et al, 2010). Western blotting confirmed the repression of HIF-1a protein by HIF-2a in the two cell lines (Figure 1a), in agreement with the data by Raval et al (2005).…”

Section: Ravalsupporting

confidence: 84%

“…siRNA oligos for the firefly luciferase gene were used as control (Ctrl; also hereafter). These siRNA oligos have been described before (Xu et al, 2010) and were purchased from Guangzhou Ribobio (Guaugdong, PR China) (other siRNAs described hereafter too). BNIP3 antibodies were purchased from Abcam (Cambridge, MA, USA).…”

Section: Ravalmentioning

confidence: 99%

“…(c) Similar experiment in VHL-defective RCC4 cells transfected with siRNA oligos for HIF-1a/2a. siRNA oligos for HIF-1a have been also described before (Xu et al, 2010). Plasmids were transfected using Fugene (Roche, Upper Bavaria, Germany) using a ratio DNA:Fugene 1:4 following the instructions by the manufacturer.…”

Section: Ravalmentioning

confidence: 99%

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Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Wang

et al. 2011

Oncogene

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Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene underlies the majority of sporadic clear cell renal cell carcinomas (CCRCCs) and is also responsible for the hereditary VHL cancer syndrome. VHL loss of function results in constitutive stabilization of hypoxia-inducible factors (HIF-1a and HIF-2a) due to insufficient proteolysis in the presence of oxygen. This activates multiple genes relevant to tumorigenesis, allowing cells to acquire further mutations and undergo malignant transformation. However, the specific role of each HIF-a subunit in CCRCC tumorigenesis is not yet well understood. The current paradigm supports that in the first stages of CCRCC formation the stabilization of HIF-1a is dominant and this limits proliferation, but later on HIF-2a increases and this induces a more aggressive cell behavior. Understanding how this transition happens is highly relevant, as it may provide novel ways to treat these cancers. Here, we show that VHL inactivation in CCRCC cells results in HIF-1a/2a-dependent downregulation of HIF-1a mRNA through direct binding of either subunit to a reverse hypoxia-response element in the HIF-1a proximal promoter. This binding activates a series of repressive histone modification marks including histone 3 lysine 27 trimethylation (H3K27me3) to make the changes stable, and if overturned reduces CCRCC cell proliferation due to excessive HIF-1a expression level. Our findings thus help understand how HIF-a subunits influence each other and also reinforce the idea that epigenetic mechanisms are a key step of CCRCC progression.

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Section: Ravalsupporting

confidence: 84%

Section: Ravalmentioning

confidence: 99%

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Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Wang

et al. 2011

Oncogene

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“…In hepatocellular carcinoma, the stabilization of HIF-1a not only induces the expression of genes involved in angiogenesis, glucidic metabolism, and survival but also causes AURKA up-regulation via its hypoxia-dependent binding to the HREs [14]. Moreover, in 2010, Xu et al [52] reported that VHL inactivation stabilizes HIF-1a inducing AURKA up-regulation in clear cell renal cell carcinoma (CCRCC) cell lines. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1 rather than inducing transcriptional activation could promote the AURKA downregulation via its binding to HREs into proximal region of AURKA promoter in BC cells under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1a significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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“…Retroviral plasmids expressing VHL30 (the longer isoform of VHL) or lentiviral plasmids expressing constitutively active forms of HIF-1␣ (carrying mutations at prolines 402 and 564) and HIF-2␣ (carrying mutations at prolines 405 and 531) have been reported previously (37,38). Lentiviral or retroviral supernatants containing these constructs were produced as described using HEK293T cells (34).…”

Section: Plasmidsmentioning

confidence: 99%

The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity

Tian

Wang

et al. 2014

Journal of Biological Chemistry

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Background:There is renewed interest in the possibility of using Vc as an anticancer agent. Results: Activation of HIF triggers a Warburg effect that renders cancer cells more sensitive to Vc-induced toxicity. Conclusion: These results provide a link between the metabolic state and the susceptibility to Vc. Significance: Our work helps to understand the preferential toxicity of Vc toward cancer cells.

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VHL Inactivation Induces HEF1 and Aurora Kinase A

Cited by 66 publications

References 30 publications

Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity

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