title: F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells.
abstract: Drug resistance remains a major clinical obstacle to successful treatment of cancer. As posttranslational modification is becoming widely recognized to affect the function of oncoproteins, targeting specific posttranslational protein modification provides an attractive strategy for anticancer drug development. CD147 is a transmembrane glycoprotein contributing to chemo-resistance of cancer cells in a variety of human malignancies. Ubiquitination is an important posttranslational modification mediating protein degradation. Degradation of oncoproteins, CD147 included, emerges as an attractive alternative for tumor inhibition. However, the ubiquitination of CD147 remains elusive. Here in this study, we found that deletion of the CD147 intracellular domain (CD147-ICD) prolonged the half-life of CD147 in HEK293T cells, and we identified that CD147-ICD interacts with FBXO22 using mass spectrometry and Western blot. Then, we demonstrated that FBXO22 mediates the polyubiquitination and degradation of CD147 by recognizing CD147-ICD. While knocking down of FBXO22 prolonged the half-life of CD147 in HEK293T cells, we found that FBXO22 regulates CD147 protein turnover in SMMC-7721, Huh-7 and A549 cells. Moreover, we found that the low level of FBXO22 contributes to the accumulation of CD147 and thereafter the cisplatin resistance of A549/DDP cells. To conclude, our study demonstrated that FBXO22 mediated the polyubiquitination and degradation of CD147 by interacting with CD147-ICD, and CD147 polyubiquitination by FBXO22 reversed cisplatin resistance of tumor cells.
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. soldier2158wubo@163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. qqqzhenyu20052008@163.com.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. cuij93@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. yxiangmind@163.com.
authors.forename: Xiang-Min
authors.initials: XM
authors.lastname: Yang
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. jinglin314@163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Jing
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. 15209262969@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. zhinanchen@fmmu.edu.cn.
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
authors.affiliation: National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. jiangjl@fmmu.edu.cn.
authors.forename: Jian-Li
authors.initials: JL
authors.lastname: Jiang
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C497886:BSG protein, human; D044783:F-Box Proteins; C561886:FBXO22 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D025821:Polyubiquitin; D051926:Basigin; D002945:Cisplatin
keywords: CD147; FBXO22; chemo-resistance; tumor; ubiquitination