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Article: MTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma

TitleMTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma
Authors
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
Citation
Oncogene, 2012, v. 31 n. 18, p. 2298-2308 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/150858
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorFan, Hen_US
dc.contributor.authorChen, Len_US
dc.contributor.authorZhang, Fen_US
dc.contributor.authorQuan, Yen_US
dc.contributor.authorSu, Xen_US
dc.contributor.authorQiu, Xen_US
dc.contributor.authorZhao, Zen_US
dc.contributor.authorKong, KLen_US
dc.contributor.authorDong, Sen_US
dc.contributor.authorSong, Yen_US
dc.contributor.authorChan, THMen_US
dc.contributor.authorGuan, XYen_US
dc.date.accessioned2012-06-26T06:12:45Z-
dc.date.available2012-06-26T06:12:45Z-
dc.date.issued2012en_US
dc.identifier.citationOncogene, 2012, v. 31 n. 18, p. 2298-2308en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttp://hdl.handle.net/10722/150858-
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.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_US
dc.relation.ispartofOncogeneen_US
dc.subjectAnimal experimenten_US
dc.subjectCancer cellen_US
dc.subjectCancer growthen_US
dc.subjectCancer inhibitionen_US
dc.subjectCarcinogenesisen_US
dc.titleMTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinomaen_US
dc.typeArticleen_US
dc.identifier.emailFan, H: fanh@seu.edu.cnen_US
dc.identifier.emailChen, L: pollyllc@hku.hk-
dc.identifier.emailChan, THM: chantim@hkucc.hku.hk-
dc.identifier.emailGuan, XY: xyguan@hkucc.hku.hk-
dc.identifier.authorityGuan, XY=rp00454en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/onc.2011.411en_US
dc.identifier.pmid21909138-
dc.identifier.scopuseid_2-s2.0-84861343066en_US
dc.identifier.hkuros203484-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84861343066&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume31en_US
dc.identifier.issue18en_US
dc.identifier.spage2298en_US
dc.identifier.epage2308en_US
dc.identifier.isiWOS:000303610800005-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridGuan, XY=7201463221en_US
dc.identifier.scopusauthoridChan, THM=26431726400en_US
dc.identifier.scopusauthoridSong, Y=35622693200en_US
dc.identifier.scopusauthoridDong, S=35788109500en_US
dc.identifier.scopusauthoridKong, KL=36106004300en_US
dc.identifier.scopusauthoridZhao, Z=23096549100en_US
dc.identifier.scopusauthoridQiu, X=35590559600en_US
dc.identifier.scopusauthoridSu, X=35590581400en_US
dc.identifier.scopusauthoridQuan, Y=35082610000en_US
dc.identifier.scopusauthoridZhang, F=55225189500en_US
dc.identifier.scopusauthoridChen, L=16174181800en_US
dc.identifier.scopusauthoridFan, H=7402553539en_US
dc.identifier.citeulike9804841-

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