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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

TitleA novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors
Authors
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
Citation
Oncogene, 2011, v. 30 n. 16, p. 1923-1935 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/139913
ISSN
2014 Impact Factor: 8.459
2014 SCImago Journal Rankings: 3.643
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorLow, JSWen_HK
dc.contributor.authorTao, Qen_HK
dc.contributor.authorNg, KMen_HK
dc.contributor.authorGoh, HKen_HK
dc.contributor.authorShu, XSen_HK
dc.contributor.authorWoo, WLen_HK
dc.contributor.authorAmbinder, RFen_HK
dc.contributor.authorSrivastava, Gen_HK
dc.contributor.authorShamay, Men_HK
dc.contributor.authorChan, ATCen_HK
dc.contributor.authorPopescu, NCen_HK
dc.contributor.authorHsieh, WSen_HK
dc.date.accessioned2011-09-23T06:01:05Z-
dc.date.available2011-09-23T06:01:05Z-
dc.date.issued2011en_HK
dc.identifier.citationOncogene, 2011, v. 30 n. 16, p. 1923-1935en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139913-
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.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectcarcinomaen_HK
dc.subjectDLC1en_HK
dc.subjectmethylationen_HK
dc.subjectp53en_HK
dc.subjectRhoGAPen_HK
dc.subjecttumor suppressor geneen_HK
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.titleA novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumorsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0950-9232&volume=30&issue=16&spage=1923&epage=1935&date=2011&atitle=A+novel+isoform+of+the+8p22+tumor+suppressor+gene+DLC1+suppresses+tumor+growth+and+is+frequently+silenced+in+multiple+common+tumorsen_US
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_HK
dc.identifier.authoritySrivastava, G=rp00365en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/onc.2010.576en_HK
dc.identifier.pmid21217778en_HK
dc.identifier.scopuseid_2-s2.0-79955466717en_HK
dc.identifier.hkuros184387en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79955466717&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume30en_HK
dc.identifier.issue16en_HK
dc.identifier.spage1923en_HK
dc.identifier.epage1935en_HK
dc.identifier.isiWOS:000289777700008-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.citeulike8623372-

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