title: hRAD9 functions as a tumor suppressor by inducing p21-dependent senescence and suppressing epithelial-mesenchymal transition through inhibition of Slug transcription.
abstract: Senescence and epithelial-mesenchymal transition (EMT) have opposing roles in tumor progression, in that, one is a barrier against tumorigenesis, whereas the other is required for invasive malignancies. Here, we report that the DNA damage response (DDR) protein hRAD9 contributes to induction of senescence and inhibition of EMT. Our data show that hRAD9 is frequently downregulated in breast and lung cancers. Loss of hRAD9 expression is associated with tumor stage in breast and lung cancers, as well as with acquisition of an invasive phenotype. Ectopic hRAD9 expression in highly invasive cancer cell lines, H1299 and MDA-MB 231, with low endogenous hRAD9 induced senescence by upregulation of nuclear p21, independent of the p53 status. Ectopic expression of hRAD9 also significantly attenuated cellular migration and invasion in vitro and tumor growth in a xenograft mouse model in vivo. In contrast, silencing hRAD9 in lower invasive cancer cell lines, A549 and MCF7, with high endogenous hRAD9 dramatically increased their migration and invasion abilities, and simultaneously activated EMT. Knockdown of hRAD9 increased, whereas ectopic expression of hRAD9 decreased, the expression of Slug. Moreover, hRAD9 directly bound to the promoter region of slug gene and repressed its transcriptional activity. Taken together, these results suggest that hRAD9 is a potential tumor suppressor in breast and lung cancers and that it is likely to function by upregulating p21 and inhibiting Slug to regulate tumorigenesis.
authors.affiliation: Institute of Basic Medical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Fan-Chih
authors.initials: FC
authors.lastname: Wen
authors.affiliation: Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan 70101, Taiwan and.
authors.forename: Tsai-Wang
authors.initials: TW
authors.lastname: Chang
authors.affiliation: Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan 70101, Taiwan and.
authors.forename: Yau-Lin
authors.initials: YL
authors.lastname: Tseng
authors.affiliation: Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan 70101, Taiwan and.
authors.forename: Janq-Chang
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Institute of Basic Medical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Department of Nutrition, College of Medicine and Nursing, Hung Kuang University, Taichung 43302, Taiwan mcchang@mail.ncku.edu.tw.
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C069930:rad9 protein