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Article: A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors
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TitleA novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors
 
AuthorsLow, JSW3 4
Tao, Q5 6 3
Ng, KM6
Goh, HK3 4
Shu, XS6
Woo, WL3
Ambinder, RF5 3 4
Srivastava, G2
Shamay, M5 3
Chan, ATC6
Popescu, NC1
Hsieh, WS5 3 4
 
Keywordscarcinoma
DLC1
methylation
p53
RhoGAP
tumor suppressor gene
 
Issue Date2011
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
CitationOncogene, 2011, v. 30 n. 16, p. 1923-1935 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2010.576
 
AbstractThe critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly downregulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38-100% of multiple primary tumors. Treatment with 5-aza-2′-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis. © 2011 Macmillan Publishers Limited All rights reserved.
 
ISSN0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
DOIhttp://dx.doi.org/10.1038/onc.2010.576
 
ISI Accession Number IDWOS:000289777700008
Funding AgencyGrant Number
A*STAR
Chinese University of Hong Kong
Singapore National Research Foundation
Ministry of Education
Funding Information:

This project was supported by an A*STAR grant (Johns Hopkins Singapore, QT/WS/RA), a Chinese University of Hong Kong grant (QT) and a grant from Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program (WS/RA). We thank Drs Bert Vogelstein, George Tsao, (Dolly Huang), Michael Obster and Guiyuan Li for some cell lines; and DSMZ (German Collection of Microorganisms & Cell Cultures) for the KYSE cell lines (Shimada et al., Cancer 69: 277-284, 1992). We also thank Drs Wenling Han, Thomas Putti, Luke Tan for some tumor samples.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLow, JSW
 
dc.contributor.authorTao, Q
 
dc.contributor.authorNg, KM
 
dc.contributor.authorGoh, HK
 
dc.contributor.authorShu, XS
 
dc.contributor.authorWoo, WL
 
dc.contributor.authorAmbinder, RF
 
dc.contributor.authorSrivastava, G
 
dc.contributor.authorShamay, M
 
dc.contributor.authorChan, ATC
 
dc.contributor.authorPopescu, NC
 
dc.contributor.authorHsieh, WS
 
dc.date.accessioned2011-09-23T06:01:05Z
 
dc.date.available2011-09-23T06:01:05Z
 
dc.date.issued2011
 
dc.description.abstractThe critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly downregulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38-100% of multiple primary tumors. Treatment with 5-aza-2′-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis. © 2011 Macmillan Publishers Limited All rights reserved.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationOncogene, 2011, v. 30 n. 16, p. 1923-1935 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2010.576
 
dc.identifier.citeulike8623372
 
dc.identifier.doihttp://dx.doi.org/10.1038/onc.2010.576
 
dc.identifier.epage1935
 
dc.identifier.hkuros184387
 
dc.identifier.isiWOS:000289777700008
Funding AgencyGrant Number
A*STAR
Chinese University of Hong Kong
Singapore National Research Foundation
Ministry of Education
Funding Information:

This project was supported by an A*STAR grant (Johns Hopkins Singapore, QT/WS/RA), a Chinese University of Hong Kong grant (QT) and a grant from Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program (WS/RA). We thank Drs Bert Vogelstein, George Tsao, (Dolly Huang), Michael Obster and Guiyuan Li for some cell lines; and DSMZ (German Collection of Microorganisms & Cell Cultures) for the KYSE cell lines (Shimada et al., Cancer 69: 277-284, 1992). We also thank Drs Wenling Han, Thomas Putti, Luke Tan for some tumor samples.

 
dc.identifier.issn0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
dc.identifier.issue16
 
dc.identifier.openurl
 
dc.identifier.pmid21217778
 
dc.identifier.scopuseid_2-s2.0-79955466717
 
dc.identifier.spage1923
 
dc.identifier.urihttp://hdl.handle.net/10722/139913
 
dc.identifier.volume30
 
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.subject.meshChromosomes, Human, Pair 8
 
dc.subject.meshGTPase-Activating Proteins - genetics
 
dc.subject.meshGenes, Tumor Suppressor
 
dc.subject.meshNeoplasms - genetics - pathology
 
dc.subject.meshTumor Suppressor Proteins - genetics
 
dc.subjectcarcinoma
 
dc.subjectDLC1
 
dc.subjectmethylation
 
dc.subjectp53
 
dc.subjectRhoGAP
 
dc.subjecttumor suppressor gene
 
dc.titleA novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors
 
dc.typeArticle
 
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Author Affiliations
  1. National Cancer Institute
  2. The University of Hong Kong
  3. Johns Hopkins Singapore
  4. National University of Singapore
  5. The Johns Hopkins School of Medicine
  6. Chinese University of Hong Kong