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Article: MTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma
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TitleMTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma
 
AuthorsFan, H3
Chen, L1 2
Zhang, F3
Quan, Y3
Su, X3
Qiu, X3
Zhao, Z1
Kong, KL1
Dong, S1
Song, Y1
Chan, THM1
Guan, XY1 2
 
KeywordsAnimal experiment
Cancer cell
Cancer growth
Cancer inhibition
Carcinogenesis
 
Issue Date2012
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
CitationOncogene, 2012, v. 31 n. 18, p. 2298-2308 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2011.411
 
AbstractDNA methyltransferase 3B (DNMT3B) mediates gene silencing via epigenetic mechanisms during hepatocellular carcinoma (HCC) progression. We aimed to identify novel targets of DNMT3B and their potential regulatory mechanisms in HCC. Metastasis suppressor 1 (MTSS1) was one of the DNMT3B targets and selected for further study. DNMT3B overexpression was detected in 81.25% of clinical HCC specimens and was negatively associated with MTSS1 in HCC cells and clinical samples. The underlying mechanism by which DNMT3B silences MTSS1 was studied using a combination of methylation-specific polymerase chain reaction (PCR) and bisulfite genome sequencing, chromatin immunoprecipitation-PCR and luciferase reporter assays. We found that the MTSS1 promoter region was sparsely methylated, and the methylation inhibitors failed to abolish DNMT3B-mediated MTSS1 silencing. DNMT3B protein bound directly to the 5'-flanking region (-865/-645) of the MTSS1 gene to inhibit its transcription. The functional role of MTSS1 was investigated using in vitro and in vivo tumorigenicity assays. As a result, MTSS1 exerted tumor suppressor effects and arrested cells in the G2/M phase, but not the G1/S phase of the cell cycle when it was depleted or overexpressed in HCC cells. Taken together, MTSS1, a novel target of DNMT3B, is repressed by DNMT3B via a DNA methylation-independent mechanism. MTSS1 was further characterized as a novel tumor suppressor gene in HCC. These findings highlight how DNMT3B regulates MTSS1, and such data may be useful for the development of new treatment options for HCC.
 
ISSN0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
DOIhttp://dx.doi.org/10.1038/onc.2011.411
 
ISI Accession Number IDWOS:000303610800005
Funding AgencyGrant Number
National Natural Science Foundation of China30971605
HKU Li Ka Shing Faculty of Medicine
Funding Information:

This work was supported by The National Natural Science Foundation of China, No. 30971605, and in part by the Dr Cheng Yu Tung Fellowships 2007/08 under the HKU Li Ka Shing Faculty of Medicine. We are grateful to Professor Dianqing WU in UConn Health Center USA for providing siRNA expression vector. We are also grateful to Dr Stephanie Ma in Department of Pathology in University of Hong Kong for helping in MTSS1 antibody.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorFan, H
 
dc.contributor.authorChen, L
 
dc.contributor.authorZhang, F
 
dc.contributor.authorQuan, Y
 
dc.contributor.authorSu, X
 
dc.contributor.authorQiu, X
 
dc.contributor.authorZhao, Z
 
dc.contributor.authorKong, KL
 
dc.contributor.authorDong, S
 
dc.contributor.authorSong, Y
 
dc.contributor.authorChan, THM
 
dc.contributor.authorGuan, XY
 
dc.date.accessioned2012-06-26T06:12:45Z
 
dc.date.available2012-06-26T06:12:45Z
 
dc.date.issued2012
 
dc.description.abstractDNA methyltransferase 3B (DNMT3B) mediates gene silencing via epigenetic mechanisms during hepatocellular carcinoma (HCC) progression. We aimed to identify novel targets of DNMT3B and their potential regulatory mechanisms in HCC. Metastasis suppressor 1 (MTSS1) was one of the DNMT3B targets and selected for further study. DNMT3B overexpression was detected in 81.25% of clinical HCC specimens and was negatively associated with MTSS1 in HCC cells and clinical samples. The underlying mechanism by which DNMT3B silences MTSS1 was studied using a combination of methylation-specific polymerase chain reaction (PCR) and bisulfite genome sequencing, chromatin immunoprecipitation-PCR and luciferase reporter assays. We found that the MTSS1 promoter region was sparsely methylated, and the methylation inhibitors failed to abolish DNMT3B-mediated MTSS1 silencing. DNMT3B protein bound directly to the 5'-flanking region (-865/-645) of the MTSS1 gene to inhibit its transcription. The functional role of MTSS1 was investigated using in vitro and in vivo tumorigenicity assays. As a result, MTSS1 exerted tumor suppressor effects and arrested cells in the G2/M phase, but not the G1/S phase of the cell cycle when it was depleted or overexpressed in HCC cells. Taken together, MTSS1, a novel target of DNMT3B, is repressed by DNMT3B via a DNA methylation-independent mechanism. MTSS1 was further characterized as a novel tumor suppressor gene in HCC. These findings highlight how DNMT3B regulates MTSS1, and such data may be useful for the development of new treatment options for HCC.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationOncogene, 2012, v. 31 n. 18, p. 2298-2308 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2011.411
 
dc.identifier.citeulike9804841
 
dc.identifier.doihttp://dx.doi.org/10.1038/onc.2011.411
 
dc.identifier.epage2308
 
dc.identifier.hkuros203484
 
dc.identifier.isiWOS:000303610800005
Funding AgencyGrant Number
National Natural Science Foundation of China30971605
HKU Li Ka Shing Faculty of Medicine
Funding Information:

This work was supported by The National Natural Science Foundation of China, No. 30971605, and in part by the Dr Cheng Yu Tung Fellowships 2007/08 under the HKU Li Ka Shing Faculty of Medicine. We are grateful to Professor Dianqing WU in UConn Health Center USA for providing siRNA expression vector. We are also grateful to Dr Stephanie Ma in Department of Pathology in University of Hong Kong for helping in MTSS1 antibody.

 
dc.identifier.issn0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
dc.identifier.issue18
 
dc.identifier.pmid21909138
 
dc.identifier.scopuseid_2-s2.0-84861343066
 
dc.identifier.spage2298
 
dc.identifier.urihttp://hdl.handle.net/10722/150858
 
dc.identifier.volume31
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofOncogene
 
dc.relation.referencesReferences in Scopus
 
dc.subjectAnimal experiment
 
dc.subjectCancer cell
 
dc.subjectCancer growth
 
dc.subjectCancer inhibition
 
dc.subjectCarcinogenesis
 
dc.titleMTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma
 
dc.typeArticle
 
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<contributor.author>Zhao, Z</contributor.author>
<contributor.author>Kong, KL</contributor.author>
<contributor.author>Dong, S</contributor.author>
<contributor.author>Song, Y</contributor.author>
<contributor.author>Chan, THM</contributor.author>
<contributor.author>Guan, XY</contributor.author>
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<description.abstract>DNA methyltransferase 3B (DNMT3B) mediates gene silencing via epigenetic mechanisms during hepatocellular carcinoma (HCC) progression. We aimed to identify novel targets of DNMT3B and their potential regulatory mechanisms in HCC. Metastasis suppressor 1 (MTSS1) was one of the DNMT3B targets and selected for further study. DNMT3B overexpression was detected in 81.25% of clinical HCC specimens and was negatively associated with MTSS1 in HCC cells and clinical samples. The underlying mechanism by which DNMT3B silences MTSS1 was studied using a combination of methylation-specific polymerase chain reaction (PCR) and bisulfite genome sequencing, chromatin immunoprecipitation-PCR and luciferase reporter assays. We found that the MTSS1 promoter region was sparsely methylated, and the methylation inhibitors failed to abolish DNMT3B-mediated MTSS1 silencing. DNMT3B protein bound directly to the 5&apos;-flanking region (-865/-645) of the MTSS1 gene to inhibit its transcription. The functional role of MTSS1 was investigated using in vitro and in vivo tumorigenicity assays. As a result, MTSS1 exerted tumor suppressor effects and arrested cells in the G2/M phase, but not the G1/S phase of the cell cycle when it was depleted or overexpressed in HCC cells. Taken together, MTSS1, a novel target of DNMT3B, is repressed by DNMT3B via a DNA methylation-independent mechanism. MTSS1 was further characterized as a novel tumor suppressor gene in HCC. These findings highlight how DNMT3B regulates MTSS1, and such data may be useful for the development of new treatment options for HCC.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong
  2. Sun Yat-Sen University
  3. Ministry of Education China