Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases

Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

doi:10.14336/ad.2015.0929

Cited by 70 publications

(34 citation statements)

References 249 publications

(297 reference statements)

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“…This indicates a reduction of H3K27me3 methylation after inhibition of the mevalonate pathway in the analyzed cell lines. This confirms the possible association with starvation and autophagy, because similar observations were reported to be associated with hypoxia [ 52 ]. Quantitative reverse transcription real time polymerase chain reaction (RT-qPCR) confirmed the GeneChip data as shown in Figure 4 .…”

Section: Resultssupporting

confidence: 89%

Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines

Karlic

Haider

Thaler

et al. 2017

IJMS

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Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP+/NADPH-relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation-markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates.

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Section: Resultssupporting

confidence: 89%

Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines

Karlic

Haider

Thaler

et al. 2017

IJMS

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“…The protein encoded by the KDM2B gene contains JmjC domain, CXXC motif, PHD domain, proline-rich region, and leucine-rich repeat. Among them, the JmjC domain is the active center that can catalyze the demethylation of H3K36me2 and H3K4me3 28–31. Recently, some studies have suggested that KDM2B regulates gene expression in a JmjC-dependent manner and may be involved in tumorigenesis; thus, it has gradually received increasing research attention 25,32.…”

Section: Discussionmentioning

confidence: 99%

Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo

Guo

et al. 2017

OTT

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Aberrant histone methylation contributes to the progression and development of many tumors. Histone methylation is a dynamic process regulated by both histone demethylase and histone methyltransferase, which ultimately alters the levels of gene transcription. However, the relationship between histone demethylase and histone methyltransferase, as well as their regulatory mechanisms in ovarian cancer development, is still unclear. Lysine-specific demethylase 2B (KDM2B) is a key demethylase of H3K36me3 and H3K4me3 that regulates gene expression and plays a role in tumorigenesis via epigenetic mechanisms. To determine the expression pattern of KDM2B in ovarian neoplasms, we analyzed the mRNA and protein levels of KDM2B and the histone methyltransferase enhancer of zester homolog 2 (EZH2) in normal, benign, borderline, and malignant ovarian tissue samples. We found that KDM2B expression was gradually increased in ovarian tumors, with the highest expression found in the malignant ovarian tissues, and the differences in KDM2B expression among the different International Federation of Gynecology and Obstetrics stages and pathological grades/types were statistically significant. Moreover, KDM2B expression was positively correlated with EZH2 expression in ovarian tissues. To determine the role of KDM2B in tumorigenesis in vitro and in vivo, we silenced KDM2B expression in ovarian cancer cells using the KDM2B short hairpin RNA expression lentivirus and established a nude mouse xenograft model. Downregulation of endogenous KDM2B decreased the expression of EZH2 and reduced the proliferation and migration of ovarian cancer cells. Loss of KDM2B suppressed ovarian tumor formation in vivo. Our results suggest that KDM2B plays an important role in the tumorigenesis of ovarian cancer, with a possible mechanism of increasing the expression of the oncogene EZH2; this indicates that certain histone methyltransferase may be positively regulated by certain histone demethylase in the epigenetic regulation of ovarian tumors. KDM2B may be a novel therapeutic target for the clinical treatment of ovarian cancer.

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“…Oxygen deficiency is a master inducer of HIF accumulation but ROS and many other stress signals can also induce HIF accumulation even at normoxia, so called pseudohypoxia ( Salminen et al, 2016 ). ROS has been found to be a contributing factor in the stabilization of HIF-1α; ultimately allowing for HIF pathway activation in a number of studies ( Chandel et al, 1998 , 2000 ; Bell et al, 2007 ).…”

Section: Ros Induced Hif Accumulationmentioning

confidence: 99%

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

Chen

Lai

Zhu³

et al. 2018

Front. Cell Dev. Biol.

198

137

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Hypoxia inducible factor (HIF) is the master oxygen sensor within cells and is central to the regulation of cell responses to varying oxygen levels. HIF activation during hypoxia ensures optimum ATP production and cell integrity, and is associated both directly and indirectly with reactive oxygen species (ROS) formation. HIF activation can either reduce ROS formation by suppressing the function of mitochondrial tricarboxylic acid cycle (TCA cycle), or increase ROS formation via NADPH oxidase (NOX), a target gene of HIF pathway. ROS is an unavoidable consequence of aerobic metabolism. In normal conditions (i.e., physioxia), ROS is produced at minimal levels and acts as a signaling molecule subject to the dedicated balance between ROS production and scavenging. Changes in oxygen concentrations affect ROS formation. When ROS levels exceed defense mechanisms, ROS causes oxidative stress. Increased ROS levels can also be a contributing factor to HIF stabilization during hypoxia and reoxygenation. In this review, we systemically review HIF activation and ROS formation in the brain during hypoxia and hypoxia/reoxygenation. We will then explore the literature describing how changes in HIF levels might provide pharmacological targets for effective ischaemic stroke treatment. HIF accumulation in the brain via HIF prolyl hydroxylase (PHD) inhibition is proposed as an effective therapy for ischaemia stroke due to its antioxidation and anti-inflammatory properties in addition to HIF pro-survival signaling. PHD is a key regulator of HIF levels in cells. Pharmacological inhibition of PHD increases HIF levels in normoxia (i.e., at 20.9% O2 level). Preconditioning with HIF PHD inhibitors show a neuroprotective effect in both in vitro and in vivo ischaemia stroke models, but post-stroke treatment with PHD inhibitors remains debatable. HIF PHD inhibition during reperfusion can reduce ROS formation and activate a number of cellular survival pathways. Given agents targeting individual molecules in the ischaemic cascade (e.g., antioxidants) fail to be translated in the clinic setting, thus far, HIF pathway targeting and thereby impacting entire physiological networks is a promising drug target for reducing the adverse effects of ischaemic stroke.

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Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases

Cited by 70 publications

References 249 publications

Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines

Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines

Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

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