title: RAP80 regulates epithelial-mesenchymal transition related with metastasis and malignancy of cancer.
abstract: Epithelial-mesenchymal transition (EMT) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the downregulation of RAP80, a well-known regulator for DNA damage response. The knockdown of RAP80 leads to EMT-like morphological changes and the increase of tumor sphere formation in non-adhesive culture. Mechanistically, RAP80 controls a reciprocal regulatory axis of ZEB1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP80 increases ZEB1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E-cadherin, p16 and p21 expression. Using in vivo metastasis analysis, RAP80 knockdown cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to controls. Interestingly, the expression level of RAP80 was positively correlated with the survival rate in lung adenocarcinoma and breast cancer patients. These findings indicate that RAP80 is a critical gatekeeper in impeding EMT-induced metastasis and malignant phenotypes of cancer as well as preserving DNA integrity.
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Park
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Sovannarith
authors.initials: S
authors.lastname: Korm
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: School of Chemical Engineering, Advanced Institute of Nanotechnology, Sungkyunkwan University, Suwon, Korea.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Cho
authors.affiliation: School of Chemical Engineering, Advanced Institute of Nanotechnology, Sungkyunkwan University, Suwon, Korea.
authors.forename: Yong Taik
authors.initials: YT
authors.lastname: Lim
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Hongtae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D056488:Histone Chaperones; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C466234:UIMC1 protein, human; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: Cancer; RAP80; ZEB1; epithelial-mesenchymal transition; metastasis