Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

Luo, Weibo; Chang, Ryan; Zhong, Jun; Pandey, Akhilesh; Semenza, Gregg L.

doi:10.1073/pnas.1217394109

Cited by 197 publications

(182 citation statements)

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“…Finally, it should be noted that, in addition to activating transcription of the RNA demethylase ALKBH5, HIFs also regulate the expression of two other O 2 -dependent dioxygenases that play key roles in breast cancer metastasis and stem cell maintenance (43,44): JMJD2C, which mediates demethylation of histones (45), and TET1, which mediates hydroxymethylation of DNA (46). It is interesting that, in the absence of HIFs, the activity of these dioxygenases should decline under hypoxic conditions as a result of reduced substrate (i.e., O 2 ) availability.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Zhang

Samanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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870

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N 6 -methyladenosine (m 6 A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m 6 A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxiainducible factor (HIF)-1α-and HIF-2α-dependent expression of AlkB homolog 5 (ALKBH5), an m 6 A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m 6 A residue in the 3′-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF-and ALKBH5-dependent manner. Insertion of the NANOG 3′-UTR into a luciferase reporter gene led to regulation of luciferase activity by O 2 , HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.hypoxia-inducible factors | metastasis | pluripotency factors | self-renewal | tumorigenesis B reast cancer has the highest incidence of all cancers affecting women (1). It is also the leading cause of cancer-related death for women worldwide (2). Although progress has been made in treating early-stage breast cancer, there is no effective strategy to prevent or treat metastasis, which is the major cause of breast cancer-related mortality (3). Within breast cancers, a small subpopulation of cells, which are designated as tumor-initiating cells or breast cancer stem cells (BCSCs), have the unique property of generating daughter BCSCs, which are capable of infinite proliferation through self-renewal, and transient amplifying cells, which are capable of a limited number of cell divisions and give rise to differentiated breast cancer cells (4, 5). Only BCSCs are capable of forming a secondary (recurrent or metastatic) tumor (5, 6). As in the case of ES cells (ESCs) (7), the BCSC phenotype is specified by the expression of core pluripotency factors, including Kruppel-like factor 4 (KLF4), Octamer-binding transcription factor 4 (OCT4), SRY-box 2 (SOX2), and NANOG (8-12). Delineation of the molecular mechanisms that regulate the BCSC phenotype is needed to better understand metastasis and design more effective therapies.Intratumoral hypoxia is a common finding in advanced cancers. The median partial pressure of oxygen (pO 2 ) within primary breast cancers is 10 mm Hg [1.4% (vol/vol) O 2 ], compared with 65 mm Hg [9.3% (vol/vol) O 2 ] in normal breast tissue (13). Hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 are heterodimeric transcriptional activators, consisting of an O 2 -regu...

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Section: Discussionmentioning

confidence: 99%

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Zhang

Samanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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870

818

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“…The shRNA oligonucleotides targeting scrambled control, or mouse HIF-1α or HIF-1β (Table S2) were annealed and ligated into AgeI/EcoRI-linearized pLKO lentiviral vector as previously described (34). Plasmid constructs were confirmed by nucleotide sequencing.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Cai

Luo

Zhan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.cardiac surgery | cardioprotection | coronary heart disease | myocardial infarction C oronary heart disease (CHD) is the leading cause of mortality in the US population, accounting for one in every six deaths, at a rate of one death from CHD every minute (1). Coronary artery stenosis due to atherosclerotic plaques results in reduced perfusion and myocardial ischemia. Plaque rupture results in complete arterial occlusion and the death of cardiac cells (myocardial infarction; MI) due to oxygen deprivation (2). Rapid reperfusion by thrombolytic therapy or percutaneous coronary intervention is the most important clinical factor to limit infarct size (IS), while at the same time reperfusion contributes to tissue injury by increasing intracellular reactive oxygen species and Ca 2+ levels (3, 4). Exposure of the heart to short (5-min) episodes of ischemia (I 5 ) and reperfusion (R 5 ) protects the heart against injury caused by a subsequent prolonged episode of ischemia and reperfusion (IR), a phenomenon known as ischemic preconditioning (IPC) (5).Although IPC was shown to have a powerful protective effect in animal models, the obvious difficulties involved in subjecting the heart to direct IPC restrict its potential clinical applications. However, the discovery that an IPC stimulus applied to the circumflex coronary artery reduced the size of an MI arising from sustained occlusion of the left anterior descending artery (6) was subsequently extended by the demonstration that the heart could be protected by su...

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“…The histone demethylase JMJD2C (KMD4C, GASC1) can demethylate trimethylated H3K9 (H3K9me3) and H3K36 (H3K36me3). 68,69 Previously known as GASC1, this histone demethylase found amplified in esophageal SCC. 70,71 Moreover, knockdown of KDM4C caused decreased proliferation of the tumor cells.…”

Section: Modulation Of Histone Demethylation Affects the Mdm2 Expressmentioning

confidence: 99%

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

Ratovitski

2014

Cell Cycle

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Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

Cited by 197 publications

References 60 publications

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

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Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

Cited by 197 publications

References 60 publications

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

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Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA