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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
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TitleThe epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors
 
AuthorsShu, XS2
Geng, H2
Li, L2
Ying, J3
Ma, C4
Wang, Y2
Poon, FF2
Wang, X2
Ying, Y2
Yeo, W2
Srivastava, G1
Tsao, SW1
Yu, J6
Sung, JJY6
Huang, S5
Chan, ATC2
Tao, Q2
 
Issue Date2011
 
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
CitationPLoS One, 2011, v. 6 n. 11, article no. e27346 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0027346
 
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.
 
ISSN1932-6203
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
 
DOIhttp://dx.doi.org/10.1371/journal.pone.0027346
 
PubMed Central IDPMC3210799
 
ISI Accession Number IDWOS:000297349700034
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorShu, XS
 
dc.contributor.authorGeng, H
 
dc.contributor.authorLi, L
 
dc.contributor.authorYing, J
 
dc.contributor.authorMa, C
 
dc.contributor.authorWang, Y
 
dc.contributor.authorPoon, FF
 
dc.contributor.authorWang, X
 
dc.contributor.authorYing, Y
 
dc.contributor.authorYeo, W
 
dc.contributor.authorSrivastava, G
 
dc.contributor.authorTsao, SW
 
dc.contributor.authorYu, J
 
dc.contributor.authorSung, JJY
 
dc.contributor.authorHuang, S
 
dc.contributor.authorChan, ATC
 
dc.contributor.authorTao, Q
 
dc.date.accessioned2012-05-29T06:14:26Z
 
dc.date.available2012-05-29T06:14:26Z
 
dc.date.issued2011
 
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.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationPLoS One, 2011, v. 6 n. 11, article no. e27346 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0027346
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0027346
 
dc.identifier.hkuros207510
 
dc.identifier.isiWOS:000297349700034
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.

 
dc.identifier.issn1932-6203
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
 
dc.identifier.issue11, article no. e27346
 
dc.identifier.pmcidPMC3210799
 
dc.identifier.pmid22087297
 
dc.identifier.scopuseid_2-s2.0-80555154347
 
dc.identifier.urihttp://hdl.handle.net/10722/148657
 
dc.identifier.volume6
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS One
 
dc.relation.referencesReferences in Scopus
 
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 tumors
 
dc.typeArticle
 
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<contributor.author>Ying, J</contributor.author>
<contributor.author>Ma, C</contributor.author>
<contributor.author>Wang, Y</contributor.author>
<contributor.author>Poon, FF</contributor.author>
<contributor.author>Wang, X</contributor.author>
<contributor.author>Ying, Y</contributor.author>
<contributor.author>Yeo, W</contributor.author>
<contributor.author>Srivastava, G</contributor.author>
<contributor.author>Tsao, SW</contributor.author>
<contributor.author>Yu, J</contributor.author>
<contributor.author>Sung, JJY</contributor.author>
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<description.abstract>BACKGROUND: 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&apos;-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.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong
  2. Prince of Wales Hospital Hong Kong
  3. Beijing Cancer Hospital
  4. Shandong University School of Medicine
  5. Central South University China
  6. Chinese University of Hong Kong