Please use this identifier to cite or link to this item: https://doi.org/10.1038/onc.2010.576
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dc.titleA novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors
dc.contributor.authorLow, J.S.W.
dc.contributor.authorTao, Q.
dc.contributor.authorNg, K.M.
dc.contributor.authorGoh, H.K.
dc.contributor.authorShu, X.-S.
dc.contributor.authorWoo, W.L.
dc.contributor.authorAmbinder, R.F.
dc.contributor.authorSrivastava, G.
dc.contributor.authorShamay, M.
dc.contributor.authorChan, A.T.C.
dc.contributor.authorPopescu, N.C.
dc.contributor.authorHsieh, W.-S.
dc.date.accessioned2014-12-12T07:09:33Z
dc.date.available2014-12-12T07:09:33Z
dc.date.issued2011-04-21
dc.identifier.citationLow, J.S.W., Tao, Q., Ng, K.M., Goh, H.K., Shu, X.-S., Woo, W.L., Ambinder, R.F., Srivastava, G., Shamay, M., Chan, A.T.C., Popescu, N.C., Hsieh, W.-S. (2011-04-21). A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors. Oncogene 30 (16) : 1923-1935. ScholarBank@NUS Repository. https://doi.org/10.1038/onc.2010.576
dc.identifier.issn09509232
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/114982
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.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1038/onc.2010.576
dc.sourceScopus
dc.subjectcarcinoma
dc.subjectDLC1
dc.subjectmethylation
dc.subjectp53
dc.subjectRhoGAP
dc.subjecttumor suppressor gene
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.description.doi10.1038/onc.2010.576
dc.description.sourcetitleOncogene
dc.description.volume30
dc.description.issue16
dc.description.page1923-1935
dc.description.codenONCNE
dc.identifier.isiut000289777700008
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