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Article: The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors

TitleThe epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
PLoS One, 2011, v. 6 n. 11, article no. e27346 How to Cite?
AbstractBACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing) proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/beta-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated beta-catenin was also observed in cell lines. CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/beta-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.
Persistent Identifierhttp://hdl.handle.net/10722/148657
ISSN
2014 Impact Factor: 3.234
2014 SCImago Journal Rankings: 1.300
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong Kong (GRF)473908
National Natural Science Foundation of China (NSFC)30928012
Funding Information:

This study was supported by grants from the Research Grants Council of Hong Kong (GRF #473908) (http://www.ugc.edu.hk/eng/rgc/index.htm) and the National Natural Science Foundation of China (NSFC #30928012) (http://www.nsfc.gov.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

 

DC FieldValueLanguage
dc.contributor.authorShu, XSen_HK
dc.contributor.authorGeng, Hen_HK
dc.contributor.authorLi, Len_HK
dc.contributor.authorYing, Jen_HK
dc.contributor.authorMa, Cen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorPoon, FFen_HK
dc.contributor.authorWang, Xen_HK
dc.contributor.authorYing, Yen_HK
dc.contributor.authorYeo, Wen_HK
dc.contributor.authorSrivastava, Gen_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorYu, Jen_HK
dc.contributor.authorSung, JJYen_HK
dc.contributor.authorHuang, Sen_HK
dc.contributor.authorChan, ATCen_HK
dc.contributor.authorTao, Qen_HK
dc.date.accessioned2012-05-29T06:14:26Z-
dc.date.available2012-05-29T06:14:26Z-
dc.date.issued2011en_HK
dc.identifier.citationPLoS One, 2011, v. 6 n. 11, article no. e27346en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148657-
dc.description.abstractBACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing) proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/beta-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated beta-catenin was also observed in cell lines. CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/beta-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS Oneen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshDNA-Binding Proteins - physiology-
dc.subject.meshEpigenesis, Genetic-
dc.subject.meshGene Silencing-
dc.subject.meshNeoplasms - genetics-
dc.subject.meshTranscription Factors - physiology-
dc.titleThe epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumorsen_HK
dc.typeArticleen_HK
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hken_HK
dc.identifier.emailTsao, SW: gswtsao@hku.hken_HK
dc.identifier.authoritySrivastava, G=rp00365en_HK
dc.identifier.authorityTsao, SW=rp00399en_HK
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1371/journal.pone.0027346en_HK
dc.identifier.pmid22087297-
dc.identifier.pmcidPMC3210799-
dc.identifier.scopuseid_2-s2.0-80555154347en_HK
dc.identifier.hkuros207510-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80555154347&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue11, article no. e27346en_HK
dc.identifier.isiWOS:000297349700034-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridTao, Q=7102578359en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.scopusauthoridHuang, S=24576547700en_HK
dc.identifier.scopusauthoridSung, JJY=35405352400en_HK
dc.identifier.scopusauthoridYu, J=35351306800en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridSrivastava, G=7202242238en_HK
dc.identifier.scopusauthoridYeo, W=7103397662en_HK
dc.identifier.scopusauthoridYing, Y=36889049800en_HK
dc.identifier.scopusauthoridWang, X=12763461000en_HK
dc.identifier.scopusauthoridPoon, FF=24577252600en_HK
dc.identifier.scopusauthoridWang, Y=36062525200en_HK
dc.identifier.scopusauthoridMa, C=54411020100en_HK
dc.identifier.scopusauthoridYing, J=12645439800en_HK
dc.identifier.scopusauthoridLi, L=54410794500en_HK
dc.identifier.scopusauthoridGeng, H=36784950400en_HK
dc.identifier.scopusauthoridShu, Xs=35277349300en_HK

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