title: NDRG2 positively regulates E-cadherin expression and prolongs overall survival in colon cancer patients.
abstract: To discover the molecular mechanism of N-Myc downstream-regulated gene 2 (NDRG2), a newly found differentiation-related tumor suppressor, the relationships between NDRG2 and E-cadherin were investigated in tumor cells and tissues. Positive correlations between the expression of E-cadherin and NDRG2 were shown in several colon cancer cell lines as well as in colon cancer tissues. According to the transcription assays using a reporter plasmid containing E-cadherin promoter region (-368~+51), NDRG2 introduction into colon cancer cell lines induced upregulation of E-cadherin promoter activity and its transcription. On the contrary, inhibition of NDRG2 expression by siRNA treatment caused the decrease of E-cadherin transcription. Snail, a zinc-finger transcriptional repressor, was shown to be a mediator of NDRG2-regulated E-cadherin expression. The enhancement of glycogen synthase kinase 3β (GSK-3β) activity by NDRG2 overexpression caused proteasomal degradation of Snail transcription factor followed by transcriptional de-repression of E-cadherin. We also found that NDRG2 could mediate cell density-regulated E-cadherin expression. The increase of NDRG2 expression with cell density preceded E-cadherin expression, and the regulation of Snail activity by GSK-3β was also related to this process.
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: Ho-Bum
authors.initials: HB
authors.lastname: Kang
authors.forename: Hyun Sun
authors.initials: HS
authors.lastname: Yim
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae Wha
authors.initials: JW
authors.lastname: Kim
mesh_terms: D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D013534:Survival; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015820:Cadherins; C466228:NDRG2 protein, human; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3