Article: The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors
| Title | The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Shu, XS5 Geng, H5 Li, L5 Ying, J2 Ma, C3 Wang, Y5 Poon, FF5 Wang, X5 Ying, Y5 Yeo, W5 Srivastava, G1 Tsao, SW1 Yu, J5 Sung, JJY5 Huang, S4 Chan, ATC5 Tao, Q5 | ||||||
| Issue Date | 2011 | ||||||
| Publisher | Public 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?] DOI: http://dx.doi.org/10.1371/journal.pone.0027346 | ||||||
| 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'-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. | ||||||
| ISSN | 1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519 | ||||||
| DOI | http://dx.doi.org/10.1371/journal.pone.0027346 | ||||||
| ISI Accession Number ID | WOS:000297349700034
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. | ||||||
| PubMed Central ID | PMC3210799 | ||||||
| References | References in Scopus |
| dc.contributor.author | Shu, XS | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Geng, H | ||||||
| dc.contributor.author | Li, L | ||||||
| dc.contributor.author | Ying, J | ||||||
| dc.contributor.author | Ma, C | ||||||
| dc.contributor.author | Wang, Y | ||||||
| dc.contributor.author | Poon, FF | ||||||
| dc.contributor.author | Wang, X | ||||||
| dc.contributor.author | Ying, Y | ||||||
| dc.contributor.author | Yeo, W | ||||||
| dc.contributor.author | Srivastava, G | ||||||
| dc.contributor.author | Tsao, SW | ||||||
| dc.contributor.author | Yu, J | ||||||
| dc.contributor.author | Sung, JJY | ||||||
| dc.contributor.author | Huang, S | ||||||
| dc.contributor.author | Chan, ATC | ||||||
| dc.contributor.author | Tao, Q | ||||||
| dc.date.accessioned | 2012-05-29T06:14:26Z | ||||||
| dc.date.available | 2012-05-29T06:14:26Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.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'-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.nature | published_or_final_version | ||||||
| dc.identifier.citation | PLoS One, 2011, v. 6 n. 11, article no. e27346 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0027346 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1371/journal.pone.0027346 | ||||||
| dc.identifier.hkuros | 207510 | ||||||
| dc.identifier.isi | WOS:000297349700034
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.issn | 1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519 | ||||||
| dc.identifier.issue | 11, article no. e27346 | ||||||
| dc.identifier.pmcid | PMC3210799 | ||||||
| dc.identifier.pmid | 22087297 | ||||||
| dc.identifier.scopus | eid_2-s2.0-80555154347 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/148657 | ||||||
| dc.identifier.volume | 6 | ||||||
| dc.language | eng | ||||||
| dc.publisher | Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | PLoS One | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.rights | Creative Commons: Attribution 3.0 Hong Kong License | ||||||
| dc.subject.mesh | DNA-Binding Proteins - physiology | ||||||
| dc.subject.mesh | Epigenesis, Genetic | ||||||
| dc.subject.mesh | Gene Silencing | ||||||
| dc.subject.mesh | Neoplasms - genetics | ||||||
| dc.subject.mesh | Transcription Factors - physiology | ||||||
| dc.title | The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong
- Beijing Cancer Hospital
- Shandong University School of Medicine
- Central South University China
- Chinese University of Hong Kong