Expression and Interaction of OTU Deubiquitinases in Hepatocellular Carcinoma
Keywords:
Hepatocellular Carcinoma, OTU Deubiquitinases, Biomarkers, Differentially Expressed Genes, Protein-Protein Interaction NetworkAbstract
Deubiquitinases (DUBs) play crucial roles in cancer progression by regulating protein ubiquitination, yet their involvement in hepatocellular carcinoma (HCC) remains underexplored. This study investigates the expression and interactions of OTU (Ovarian Tumor) DUBs in HCC to evaluate their potential as diagnostic, prognostic, and therapeutic markers. Gene Expression Omnibus (GEO) microarray datasets were analyzed using GEO2R to compare gene expression profiles between HCC and normal liver tissues. Differentially expressed genes (DEGs) were identified based on stringent criteria of log fold change (logFC) > 2.0 and adjusted P-value < 0.05. The expression profiles of 16 OTU DUBs were examined, and a protein-protein interaction (PPI) network was constructed incorporating overlapping DEGs and selected OTU DUBs. Kaplan-Meier (KM) survival analysis was performed using patient data from The Cancer Genome Atlas (TCGA) to assess prognostic significance. The analysis identified OTULIN as the only OTU DUB meeting DEG criteria, showing significant downregulation. OTUB1, OTUB2, and OTUD6B exhibited near-threshold expression changes and were included for further analysis due to their potential relevance. The PPI network revealed OTUB1 and OTUB2 as integral components of the HCC interactome, connecting to key regulators such as FOXM1 and ERα, respectively. KM survival analysis demonstrated that high expression of OTUB1 and OTUB2 correlates with poorer overall survival, whereas OTULIN and OTUD6B showed no significant impact. These findings highlight the potential roles of OTUB1 and OTUB2 in modulating HCC-related pathways, positioning them as promising candidates for therapeutic exploration, despite their limitations as diagnostic or prognostic marker.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, & Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians. 2021;71(3):209–249. https://doi.org/10.3322/caac.21660
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, & Finn RS. Hepatocellular carcinoma. Nature reviews. Disease primers. 2021;7(1):6.
https://doi.org/10.1038/s41572-020-00240-3
Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR, & Heimbach JK. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.). 2018;68(2):723–750. https://doi.org/10.1002/hep.29913
Villanueva A. Hepatocellular Carcinoma. The New England journal of medicine. 2019;380(15):1450–1462. https://doi.org/10.1056/NEJMra1713263
Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, Waljee AK, & Singal AG. Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology. 2018;154(6):1706–1718.e1.
https://doi.org/10.1053/j.gastro.2018.01.064
Komander D & Rape M. The ubiquitin code. Annual review of biochemistry. 2012;81:203–229.
https://doi.org/10.1146/annurev-biochem-060310-170328
Swatek KN & Komander D. Ubiquitin modifications. Cell research. 2016;26(4):399–422.
https://doi.org/10.1038/cr.2016.39
Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK & Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123(5):773–786. https://doi.org/10.1016/j.cell.2005.11.007
Popovic D, Vucic D & Dikic I. Ubiquitination in disease pathogenesis and treatment. Nature medicine. 2014;20(11):1242–1253. https://doi.org/10.1038/nm.3739
Du J, Fu L, Sui Y, et al. The function and regulation of OTU deubiquitinases. Front. Med. 2020;14:542–563 (2020). https://doi.org/10.1007/s11684-019-0734-4
Shi Y, Wang X, Wang J, Wang X, Zhou H & Zhang L. The dual roles of A20 in cancer. Cancer Letters. 2021;511:26–35. https://doi.org/10.1016/j.canlet.2021.04.017
Sun XX, Challagundla KB & Dai MS. Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. The EMBO Journal. 2012;31(3):576–592. https://doi.org/10.1038/emboj.2011.434
Zhou K, Mai H, Zheng S, Cai W, Yang X, Chen Z & Zhan B. OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in renal cell carcinoma. Cell & bioscience. 2020;10:50. https://doi.org/10.1186/s13578-020-00408-0
Hu G, Yang J, Zhang H, Huang Z & Yang H. OTUB2 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells by PJA1 Deubiquitylation. Cellular and Molecular Bioengineering. 2022;15(3):281–292. https://doi.org/10.1007/s12195-022-00720-4
Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, Wauer T, Hospenthal MK, Gyrd-Hansen M, Krappmann D, Hofmann K & Komander D. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell. 2013;153(6):1312–1326. https://doi.org/10.1016/j.cell.2013.05.014
Enesa K, Zakkar M, Chaudhury H, Luong leA, Rawlinson L, Mason JC, Haskard DO, Dean JL & Evans PC. NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling. The Journal of biological chemistry. 2008;283(11):7036–7045.
https://doi.org/10.1074/jbc.M708690200
Kong S, Xue H, Li Y, Li P, Ma F, Liu M & Li W. The long noncoding RNA OTUD6B-AS1 enhances cell proliferation and the invasion of hepatocellular carcinoma cells through modulating GSKIP/Wnt/β-catenin signalling via the sequestration of miR-664b-3p. Experimental Cell Research. 2020;395(1):112180.
https://doi.org/10.1016/j.yexcr.2020.112180
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S & Soboleva A. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Research. 2013;41(Database issue):D991–D995.
https://doi.org/10.1093/nar/gks1193
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, Bork P, Jensen LJ & von Mering C. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Research. 2023;51(D1):D638–D646. https://doi.org/10.1093/nar/gkac1000
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B & Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Research. 2003;13(11):2498–2504. https://doi.org/10.1101/gr.1239303
Bader GD & Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC bioinformatics. 2003;4:2.
https://doi.org/10.1186/1471-2105-4-2
Győrffy B. Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors. Innovation (Cambridge (Mass.). 2004;5(3): 100625. https://doi.org/10.1016/j.xinn.2024.100625
Tomczak K, Czerwińska P & Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemporary oncology (Poznan, Poland). 2015;19(1A):A68–A77. https://doi.org/10.5114/wo.2014.47136
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C & Schultz N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer discovery. 2012;2(5):401–404.
https://doi.org/10.1158/2159-8290.CD-12-0095
Che Rosli AF, Abdul Razak SR & Zulkifle N. Bioinformatics analysis of differentially expressed genes in liver cancer for identification of key genes and pathways. Malaysian Journal of Medicine and Health Sciences. 2019;15(SP2):18-24
Módos D, Bulusu KC, Fazekas D, Kubisch J, Brooks J, Marczell I, Szabó PM, Vellai T, Csermely P, Lenti K, Bender A & Korcsmáros T. Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies. NPJ Systems Biology and Applications. 2017;3:2. https://doi.org/10.1038/s41540-017-0003-6
Hu G, Yan Z, Zhang C, Cheng M, Yan Y, Wang Y, Deng L, Lu Q & Luo S. FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression. Journal of Experimental & Clinical Cancer Research : CR. 2019;38(1):188.
https://doi.org/10.1186/s13046-019-1202-3
Song BN & Chu IS. A gene expression signature of FOXM1 predicts the prognosis of hepatocellular carcinoma. Experimental & Molecular Medicine. 2018;50(1):e418. https://doi.org/10.1038/emm.2017.159
Bhat M, Pasini E, Pastrello C, Angeli M, Baciu C, Abovsky M, Coffee A, Adeyi O, Kotlyar M & Jurisica I. Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis. Frontiers in Oncology. 2021;11:777834.
https://doi.org/10.3389/fonc.2021.777834
Jeon Y, Yoo JE, Rhee H, Kim YJ, Il Kim G, Chung T, Yoon S, Shin B, Woo HG & Park YN. YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior. Experimental & Molecular Medicine. 2021;53(6):1055–1067.
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