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Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response.

ABSTRACT: Adaptation to tumor hypoxia is mediated in large part by changes in protein expression. These are driven by multiple pathways, including activation of the hypoxia inducible factor-1 (HIF-1) transcription factor and the PKR-like endoplasmic reticulum kinase PERK, a component of the unfolded protein response. Through gene expression profiling we discovered that induction of the HIF-1 target gene CA9 was defective in mouse embryo fibroblasts derived from mice harboring an eIF2alpha S51A knock-in mutation. This finding was confirmed in two isogenic human cell lines with an engineered defect in eIF2alpha phosphorylation. We show that impaired CA9 expression was not due to changes in HIF activity or CA9 mRNA stability. Using chromatin immunoprecipitation we show that the eIF2alpha-dependent translationally regulated gene ATF4 binds directly to the CA9 promoter and is associated with loss of the transcriptional repressive histone 3 lysine 27 tri-methylation mark. Loss or overexpression of ATF4 confirmed its role in CA9 induction during hypoxia. Our data indicate that expression of CA9 is regulated through both the HIF-1 and unfolded protein response hypoxia response pathways in vitro and in vivo.

SUBMITTER: van den Beucken T

PROVIDER: S-EPMC2782014 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response.

van den Beucken Twan T Koritzinsky Marianne M Niessen Hanneke H Dubois Ludwig L Savelkouls Kim K Mujcic Hilda H Jutten Barry B Kopacek Juraj J Pastorekova Sylvia S van der Kogel Albert J AJ Lambin Philippe P Voncken Willem W Rouschop Kasper M A KM Wouters Bradly G BG

The Journal of biological chemistry 20090629 36

Adaptation to tumor hypoxia is mediated in large part by changes in protein expression. These are driven by multiple pathways, including activation of the hypoxia inducible factor-1 (HIF-1) transcription factor and the PKR-like endoplasmic reticulum kinase PERK, a component of the unfolded protein response. Through gene expression profiling we discovered that induction of the HIF-1 target gene CA9 was defective in mouse embryo fibroblasts derived from mice harboring an eIF2alpha S51A knock-in mu ...[more]

PMID: 19564335

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Project description:AIM:To study the expression of carbonic anhydrase (CA) 9 in human hepatocellular carcinoma (HCC) cells. METHODS:We studied CA9 protein, CA9 mRNA and hypoxia-inducible factor-1 alpha (HIF-1?) protein levels in Hep3B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia (24 h 0.1% O(2)) without or with interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-?) and transforming growth factor-beta (TGF-?) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation. RESULTS:The tumour cell line analysed showed a strong hypoxic CA9 mRNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1? protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-? and TGF-?, under normoxic conditions significantly increased the carbonic anhydrase 9 expression level at both the protein and mRNA level, almost doubling the CA9 mRNA and CA9 and HIF-1? protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-? and TGF-?, positively influence CA9 expression under both normoxic and hypoxic conditions. CONCLUSION:These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provide evidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive disease regulator in human cancer.

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Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response.

Publications

Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response.

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