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Article: Epigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cells

TitleEpigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cells
Authors
Keywords5-aza-2′-deoxycytidine
ChIP
CpG island
DNA methyltransferase 1
Hydralazine
RNA interference
Issue Date2008
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yexcr
Citation
Experimental Cell Research, 2008, v. 314 n. 8, p. 1823-1830 How to Cite?
AbstractMammalian stanniocalcin-2 (STC2) is a secreted glycoprotein hormone with a putative role in unfolded protein response and apoptosis. Here we reported that STC2 expression was sporadically abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines revealed that CpG dinucleotides in STC2 promoter was methylated in human ovarian epithelial cancer (SKOV3, OVCAR3 and CaOV3), pancreatic cancer (BxP3), colon adenoma (HT29), and leukemia (Jurkat cells). STC2 CpG island hypermethylation was accompanied with a low basal STC2 expression level. Treatment of these cancer cells with 5-aza-2′-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation significantly induced STC2 expression. Using SKOV3 cells as a model, the link between DNA demethylation and STC2 expression was consistently demonstrated with hydralazine treatment, which was shown to reduce the protein level of DNA methyltransferase 1 (DNMT1) but stimulated STC2 expression. Two human normal surface ovarian cell-lines (i.e. IOSE 29 and 398) showed no methylation at CpG dinucleotides in the examined promoter region and were accompanied with high basal STC2 levels. Hypoxia stimulated STC2 expression in SKOV3 cells was markedly increased in 5-aza-CdR pretreated cells, showing that DNA methylation may hinder the HIF-1 mediated activation. To elucidate this possibility, RNA interference studies confirmed that endogenous HIF-1α was a key factor for STC2 gene activation as well as in the synergistic induction of STC2 expression in 5-aza-CdR pretreated cells. Chromatin immunoprecipitation (ChIP) assay demonstrated the binding of HIF-1α to STC2 promoter. The binding was increased in 5-aza-CdR pretreated cells. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression. © 2008 Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/89229
ISSN
2015 Impact Factor: 3.378
2015 SCImago Journal Rankings: 1.900
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLaw, AYSen_HK
dc.contributor.authorLai, KPen_HK
dc.contributor.authorIp, CKMen_HK
dc.contributor.authorWong, ASTen_HK
dc.contributor.authorWagner, GFen_HK
dc.contributor.authorWong, CKCen_HK
dc.date.accessioned2010-09-06T09:54:11Z-
dc.date.available2010-09-06T09:54:11Z-
dc.date.issued2008en_HK
dc.identifier.citationExperimental Cell Research, 2008, v. 314 n. 8, p. 1823-1830en_HK
dc.identifier.issn0014-4827en_HK
dc.identifier.urihttp://hdl.handle.net/10722/89229-
dc.description.abstractMammalian stanniocalcin-2 (STC2) is a secreted glycoprotein hormone with a putative role in unfolded protein response and apoptosis. Here we reported that STC2 expression was sporadically abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines revealed that CpG dinucleotides in STC2 promoter was methylated in human ovarian epithelial cancer (SKOV3, OVCAR3 and CaOV3), pancreatic cancer (BxP3), colon adenoma (HT29), and leukemia (Jurkat cells). STC2 CpG island hypermethylation was accompanied with a low basal STC2 expression level. Treatment of these cancer cells with 5-aza-2′-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation significantly induced STC2 expression. Using SKOV3 cells as a model, the link between DNA demethylation and STC2 expression was consistently demonstrated with hydralazine treatment, which was shown to reduce the protein level of DNA methyltransferase 1 (DNMT1) but stimulated STC2 expression. Two human normal surface ovarian cell-lines (i.e. IOSE 29 and 398) showed no methylation at CpG dinucleotides in the examined promoter region and were accompanied with high basal STC2 levels. Hypoxia stimulated STC2 expression in SKOV3 cells was markedly increased in 5-aza-CdR pretreated cells, showing that DNA methylation may hinder the HIF-1 mediated activation. To elucidate this possibility, RNA interference studies confirmed that endogenous HIF-1α was a key factor for STC2 gene activation as well as in the synergistic induction of STC2 expression in 5-aza-CdR pretreated cells. Chromatin immunoprecipitation (ChIP) assay demonstrated the binding of HIF-1α to STC2 promoter. The binding was increased in 5-aza-CdR pretreated cells. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression. © 2008 Elsevier Inc. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yexcren_HK
dc.relation.ispartofExperimental Cell Researchen_HK
dc.subject5-aza-2′-deoxycytidineen_HK
dc.subjectChIPen_HK
dc.subjectCpG islanden_HK
dc.subjectDNA methyltransferase 1en_HK
dc.subjectHydralazineen_HK
dc.subjectRNA interferenceen_HK
dc.titleEpigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0014-4827&volume=314&spage=1823&epage=1830&date=2008&atitle=Epigenetic+and+HIF-1+regulation+of+stanniocalcin-2+expression+in+human+cancer+cellsen_HK
dc.identifier.emailLai, KP: ballllai@hotmail.comen_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityLai, KP=rp01753en_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.yexcr.2008.03.001en_HK
dc.identifier.pmid18394600-
dc.identifier.scopuseid_2-s2.0-42649112018en_HK
dc.identifier.hkuros144165en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-42649112018&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume314en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1823en_HK
dc.identifier.epage1830en_HK
dc.identifier.isiWOS:000255624300016-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLaw, AYS=16175363700en_HK
dc.identifier.scopusauthoridLai, KP=7402135707en_HK
dc.identifier.scopusauthoridIp, CKM=23987652100en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK
dc.identifier.scopusauthoridWagner, GF=7404372679en_HK
dc.identifier.scopusauthoridWong, CKC=35276549400en_HK
dc.identifier.citeulike7501805-

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