title: Disruption of FAT10-MAD2 binding inhibits tumor progression.
abstract: FAT10 (HLA-F-adjacent transcript 10) is a ubiquitin-like modifier that is commonly overexpressed in various tumors. It was found to play a role in mitotic regulation through its interaction with mitotic arrest-deficient 2 (MAD2). Overexpression of FAT10 promotes tumor growth and malignancy. Here, we identified the MAD2-binding interface of FAT10 to be located on its first ubiquitin-like domain whose NMR structure thus was determined. We further proceeded to demonstrate that disruption of the FAT10-MAD2 interaction through mutation of specific MAD2-binding residues did not interfere with the interaction of FAT10 with its other known interacting partners. Significantly, ablation of the FAT10-MAD2 interaction dramatically limited the promalignant capacity of FAT10, including promoting tumor growth in vivo and inducing aneuploidy, proliferation, migration, invasion, and resistance to apoptosis in vitro. Our results strongly suggest that the interaction of FAT10 with MAD2 is a key mechanism underlying the promalignant property of FAT10 and offer prospects for the development of anticancer strategies.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore;
authors.forename: Steven Setiawan
authors.initials: SS
authors.lastname: Theng
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119077, Singapore;
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore; Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore;
authors.forename: Way-Champ
authors.initials: WC
authors.lastname: Mah
authors.affiliation: National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore; Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore;
authors.forename: Cheryl
authors.initials: C
authors.lastname: Chan
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore;
authors.forename: Jingli
authors.initials: J
authors.lastname: Zhuo
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore;
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119077, Singapore;
authors.forename: Haina
authors.initials: H
authors.lastname: Qin
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119077, Singapore;
authors.forename: Liangzhong
authors.initials: L
authors.lastname: Lim
authors.affiliation: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; and.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Chong
authors.affiliation: National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119077, Singapore; dbssjx@nus.edu.sg caroline_lee@nuhs.edu.sg.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore; Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; Duke-National University of Singapore Graduate Medical School, Singapore 169547, Singapore dbssjx@nus.edu.sg caroline_lee@nuhs.edu.sg.
authors.forename: Caroline G
authors.initials: CG
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002469:Cell Separation; D043171:Chromosomal Instability; D018450:Disease Progression; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D064246:Mad2 Proteins / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; C109184:UBD protein, human; D014452:Ubiquitins
keywords: FAT10; aneuploidy; cancer progression; chromosomal instability; ubiquitin