PMID- 32140187 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240423 IS - 1878-5077 (Print) IS - 1878-5085 (Electronic) IS - 1878-5077 (Linking) VI - 11 IP - 1 DP - 2020 Mar TI - Label-free quantitative identification of abnormally ubiquitinated proteins as useful biomarkers for human lung squamous cell carcinomas. PG - 73-94 LID - 10.1007/s13167-019-00197-8 [doi] AB - BACKGROUND: Ubiquitination is an important molecular event in lung squamous cell carcinoma (LSCC), which currently is mainly studied in nonsmall cell lung carcinoma cell models but lacking of ubiquitination studies on LSCC tissues. Here, we presented the ubiquitinated protein profiles of LSCC tissues to explore ubiquitination-involved molecular network alterations and identify abnormally ubiquitinated proteins as useful biomarkers for predictive, preventive, and personalized medicine (PPPM) in LSCC. METHODS: Anti-ubiquitin antibody-based enrichment coupled with LC-MS/MS was used to identify differentially ubiquitinated proteins (DUPs) between LSCC and control tissues, followed by integrative omics analyses to identify abnormally ubiquitinated protein biomarkers for LSCC. RESULTS: Totally, 400 DUPs with 654 ubiquitination sites were identified,, and motifs A-X (1/2/3)-K* were prone to be ubiquitinated in LSCC tissues. Those DUPs were involved in multiple molecular network systems, including the ubiquitin-proteasome system (UPS), cell metabolism, cell adhesion, and signal transduction. Totally, 44 hub molecules were revealed by protein-protein interaction network analysis, followed by survival analysis in TCGA database (494 LSCC patients and 20,530 genes) to obtain 18 prognosis-related mRNAs, of which the highly expressed mRNAs VIM and IGF1R were correlated with poorer prognosis, while the highly expressed mRNA ABCC1 was correlated with better prognosis. VIM-encoded protein vimentin and ABCC1-encoded protein MRP1 were increased in LSCC, which were all associated with poor prognosis. Proteasome-inhibited experiments demonstrated that vimentin and MRP1 were degraded through UPS. Quantitative ubiquitinomics found ubiquitination level was decreased in vimentin and increased in MRP1 in LSCC. These findings showed that the increased vimentin in LSCC might be derived from its decreased ubiquitination level and that the increased MRP1 in LSCC might be derived from its protein synthesis > degradation. GSEA and co-expression gene analyses revealed that VIM and MRP1 were involved in multiple crucial biological processes and pathways. Further, TRIM2 and NEDD4L were predicted as E3 ligases to regulate ubiquitination of vimentin and MRP1, respectively. CONCLUSION: These findings revealed ubiquitinomic variations and molecular network alterations in LSCC, which is in combination with multiomics analysis to identify ubiquitination-related biomarkers for in-depth insight into the molecular mechanism and therapeutic targets and for prediction, diagnosis, and prognostic assessment of LSCC. CI - (c) The Author(s) 2020. FAU - Lu, Miaolong AU - Lu M AD - 1Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 AD - 2Hunan Engineering Laboratory for Structural Biology and Drug Design, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 AD - 3State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 FAU - Chen, Wei AU - Chen W AD - Shanghai Applied Protein Technology, Shanghai, 200233 People's Republic of China. FAU - Zhuang, Wei AU - Zhuang W AD - 5Department of Thoracic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 FAU - Zhan, Xianquan AU - Zhan X AUID- ORCID: 0000-0002-4984-3549 AD - 1Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 AD - 2Hunan Engineering Laboratory for Structural Biology and Drug Design, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 AD - 3State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 AD - 6Department of Oncology, Xiangya Hospital, Central South University, 88 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 AD - 7National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 88 Xiangya Road, Changsha, 410008 Hunan People's Republic of China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 LA - eng GR - R01 AA020610/AA/NIAAA NIH HHS/United States PT - Journal Article DEP - 20200104 PL - Switzerland TA - EPMA J JT - The EPMA journal JID - 101517307 PMC - PMC7028901 OTO - NOTNLM OT - Cell adhesion OT - Lung squamous cell carcinoma OT - Metabolic reprogramming OT - Multiomics OT - Predictive preventive personalized medicine (PPPM) OT - Quantitative ubiquitinomics OT - Signal transduction OT - Tumor inflammation OT - Ubiqitination-related biomarker OT - Ubiquitin-proteasome system (UPS) COIS- Competing interestsThe authors declare that they have no conflict of interest. EDAT- 2020/03/07 06:00 MHDA- 2020/03/07 06:01 PMCR- 2020/01/04 CRDT- 2020/03/07 06:00 PHST- 2019/10/06 00:00 [received] PHST- 2019/12/12 00:00 [accepted] PHST- 2020/03/07 06:00 [entrez] PHST- 2020/03/07 06:00 [pubmed] PHST- 2020/03/07 06:01 [medline] PHST- 2020/01/04 00:00 [pmc-release] AID - 197 [pii] AID - 10.1007/s13167-019-00197-8 [doi] PST - epublish SO - EPMA J. 2020 Jan 4;11(1):73-94. doi: 10.1007/s13167-019-00197-8. eCollection 2020 Mar.