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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

A Novel Risk Model of SUMOylation-related Genes Associated with Prognosis in Endometrial Cancer

Author(s): Yajie Lei, Qing Xu, Yixin Chen, Haoran Li and Xi Cheng*

Volume 26, Issue 3, 2023

Published on: 27 July, 2022

Page: [595 - 609] Pages: 15

DOI: 10.2174/1386207325666220519114248

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Endometrial cancer is ranked fourth in women's cancers worldwide. SUMOylation is a process of post-translational modification and some evidence indicate that SUMOylation may influence the occurrence and development of cancer. Until now, the prognostic value of SUMOylation-related genes in endometrial cancer remains unclear. Therefore, we aimed at exploring the prognostic value of SUMOylation-related genes in endometrial cancer in this study.

Methods: The transcriptome of endometrial cancer from TCGA database was downloaded and then differentially expressed SUMOylation-related genes were extracted. The risk model was constructed with the use of the least absolute shrinkage and selection operator Cox regression. Samples were divided into low-risk and high-risk group based on the risk score. Survival analysis and Cox analysis were performed between groups. A validation cohort from Fudan University Shanghai Cancer Center were obtained to verify the model. Gene ontology and Kyoto Encylopedia of Genes and Genomes analyses were conducted based on differentially expressed genes between groups.

Results: Samples in low-risk group possess better outcome than in high-risk group. (P<0.001) The results of univariate (P<0.001) and multivariate (P=0.018) analysis showed that the risk score was independently correlated to worse outcome for patients with endometrial cancer. In Fudan University Shanghai Cancer Center validation cohort, the low-risk group possessed better survival outcome than the high-risk group (P=0.0393). Functional analysis demonstrated that most of the immune cell infiltration levels and immune pathways activity in low-risk group were higher than in high-risk group.

Conclusions: In short, the SUMOylation-related signature had good predictability in endometrial cancer and SUMOylation-related genes play important roles in tumour immunity. Also, our study might have some merits in elucidating potential mechanism of SUMOylation in endometrial cancer.

Keywords: Endometrial cancer, SUMOylation, TCGA, risk model, survival, tumor immunity.

Graphical Abstract
[1]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70(1): 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Brooks RA, Fleming GF, Lastra RR, et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin 2019; 69(4): 258-79.
[http://dx.doi.org/10.3322/caac.21561] [PMID: 31074865]
[3]
Lu KH, Broaddus RR. Endometrial cancer. N Engl J Med 2020; 383(21): 2053-64.
[http://dx.doi.org/10.1056/NEJMra1514010] [PMID: 33207095]
[4]
Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016; 66(4): 271-89.
[http://dx.doi.org/10.3322/caac.21349] [PMID: 27253694]
[5]
Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet 2016; 387(10023): 1094-108.
[http://dx.doi.org/10.1016/S0140-6736(15)00130-0] [PMID: 26354523]
[6]
Yau TY, Molina O, Courey AJ. SUMOylation in development and neurodegeneration. Development 2020; 147(6): dev175703.
[http://dx.doi.org/10.1242/dev.175703] [PMID: 32188601]
[7]
Liu S, Wang L, Jiang D, et al. Sumoylation as an emerging target in therapeutics against cancer. Curr Pharm Des 2020; 26(37): 4764-76.
[http://dx.doi.org/10.2174/1381612826666200622124134] [PMID: 32568016]
[8]
Han ZJ, Feng YH, Gu BH, Li YM, Chen H. The post-translational modification, SUMOylation, and cancer. (Review). Int J Oncol 2018; 52(4): 1081-94.
[http://dx.doi.org/10.3892/ijo.2018.4280] [PMID: 29484374]
[9]
Guo M, Huang BX. Integration of phosphoproteomic, chemical, and biological strategies for the functional analysis of targeted protein phosphorylation. Proteomics 2013; 13(3-4): 424-37.
[http://dx.doi.org/10.1002/pmic.201200274] [PMID: 23125184]
[10]
Kim W, Bennett EJ, Huttlin EL, et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 2011; 44(2): 325-40.
[http://dx.doi.org/10.1016/j.molcel.2011.08.025] [PMID: 21906983]
[11]
Lamoliatte F, McManus FP, Maarifi G, Chelbi-Alix MK, Thibault P. Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification. Nat Commun 2017; 8(1): 14109.
[http://dx.doi.org/10.1038/ncomms14109] [PMID: 28098164]
[12]
Biggar KK, Li SS. Non-histone protein methylation as a regulator of cellular signalling and function. Nat Rev Mol Cell Biol 2015; 16(1): 5-17.
[http://dx.doi.org/10.1038/nrm3915] [PMID: 25491103]
[13]
Choudhary C, Kumar C, Gnad F, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009; 325(5942): 834-40.
[http://dx.doi.org/10.1126/science.1175371] [PMID: 19608861]
[14]
Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein acetylation. Biochim Biophys Acta 2016; 1864(10): 1372-401.
[http://dx.doi.org/10.1016/j.bbapap.2016.06.007] [PMID: 27296530]
[15]
Menzies KJ, Zhang H, Katsyuba E, Auwerx J. Protein acetylation in metabolism - metabolites and cofactors. Nat Rev Endocrinol 2016; 12(1): 43-60.
[http://dx.doi.org/10.1038/nrendo.2015.181] [PMID: 26503676]
[16]
Verdin E, Ott M. 50 years of protein acetylation: From gene regulation to epigenetics, metabolism and beyond. Nat Rev Mol Cell Biol 2015; 16(4): 258-64.
[http://dx.doi.org/10.1038/nrm3931] [PMID: 25549891]
[17]
Bettermann K, Benesch M, Weis S, Haybaeck J. SUMOylation in carcinogenesis. Cancer Lett 2012; 316(2): 113-25.
[http://dx.doi.org/10.1016/j.canlet.2011.10.036] [PMID: 22138131]
[18]
Eifler K, Vertegaal ACO. SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem Sci 2015; 40(12): 779-93.
[http://dx.doi.org/10.1016/j.tibs.2015.09.006] [PMID: 26601932]
[19]
Seeler JS, Dejean A. SUMO and the robustness of cancer. Nat Rev Cancer 2017; 17(3): 184-97.
[http://dx.doi.org/10.1038/nrc.2016.143] [PMID: 28134258]
[20]
Vlachostergios PJ, Papandreou CN. The role of the Small Ubiquitin-Related Modifier (SUMO) pathway in prostate cancer. Biomolecules 2012; 2(2): 240-55.
[http://dx.doi.org/10.3390/biom2020240] [PMID: 24970135]
[21]
Zubiete-Franco I, García-Rodríguez JL, Lopitz-Otsoa F, et al. SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer. EBioMedicine 2019; 40: 406-21.
[http://dx.doi.org/10.1016/j.ebiom.2018.12.031] [PMID: 30594553]
[22]
Lu W, Wang Q, Xu C, et al. SUMOylation is essential for Sirt2 tumor-suppressor function in neuroblastoma. Neoplasia 2021; 23(1): 129-39.
[http://dx.doi.org/10.1016/j.neo.2020.11.013] [PMID: 33316537]
[23]
Xia L, Jiang Y, Zhang XH, et al. SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leuke-mia cells. Cell Death Dis 2021; 12(1): 101.
[http://dx.doi.org/10.1038/s41419-021-03400-9] [PMID: 33473116]
[24]
Fu C, Yuan G, Yang ST, Zhang D, Yang S. RGS12 represses oral cancer via the phosphorylation and SUMOylation of PTEN. J Dent Res 2021; 100(5): 522-31.
[http://dx.doi.org/10.1177/0022034520972095] [PMID: 33198557]
[25]
Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004; 40(3): 667-76.
[http://dx.doi.org/10.1002/hep.20375] [PMID: 15349906]
[26]
Tan MY, Mu XY, Liu B, et al. SUMO-specific protease 2 suppresses cell migration and invasion through inhibiting the expression of MMP13 in bladder cancer cells. Cell Physiol Biochem 2013; 32(3): 542-8.
[http://dx.doi.org/10.1159/000354458] [PMID: 24008762]
[27]
Pei H, Chen L, Liao QM, et al. SUMO-specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degrada-tion. Exp Ther Med 2018; 16(6): 5359-65.
[http://dx.doi.org/10.3892/etm.2018.6838] [PMID: 30542495]
[28]
Zhang J, Chen Z, Zhou Z, Yang P, Wang CY. Sumoylation Modulates the Susceptibility to Type 1 Diabetes. Adv Exp Med Biol 2017; 963: 299-322.
[http://dx.doi.org/10.1007/978-3-319-50044-7_18] [PMID: 28197920]
[29]
Alzolibani AA, Settin A, Ahmed AA, Ismail H, Elhefni N, Al Robaee AA. Genetic polymorphisms of NFκB1 -94 del/ins ATTG, NFκB1A 2758 A>G and SUMO rs237025 G>A in psoriasis. Int J Health Sci (Qassim) 2015; 9(1): 25-33.
[http://dx.doi.org/10.12816/0024680] [PMID: 25901130]
[30]
Chen S, Yang T, Liu F, et al. Inflammatory factor-specific sumoylation regulates NF-κB signalling in glomerular cells from diabetic rats. Inflamm Res 2014; 63(1): 23-31.
[http://dx.doi.org/10.1007/s00011-013-0675-3] [PMID: 24173240]
[31]
Liang JX, Gao W, Zeng XW, et al. SUMO4 small interfering RNA attenuates invasion and migration via the JAK2/STAT3 pathway in non-small cell lung cancer cells. Oncol Lett 2020; 20(5): 225.
[http://dx.doi.org/10.3892/ol.2020.12088] [PMID: 32968447]
[32]
Jena S, Lee WP, Doherty D, Thompson PD. PIAS4 represses vitamin D receptor-mediated signaling and acts as an E3-SUMO ligase to-wards vitamin D receptor. J Steroid Biochem Mol Biol 2012; 132(1-2): 24-31.
[http://dx.doi.org/10.1016/j.jsbmb.2012.04.006] [PMID: 22564762]
[33]
Morris JR, Boutell C, Keppler M, et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 2009; 462(7275): 886-90.
[http://dx.doi.org/10.1038/nature08593] [PMID: 20016594]
[34]
Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote re-sponses to DNA double-strand breaks. Nature 2009; 462(7275): 935-9.
[http://dx.doi.org/10.1038/nature08657] [PMID: 20016603]
[35]
Sun L, Li H, Chen J, et al. PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. J Cell Sci 2013; 126(Pt 17): 3939-47.
[http://dx.doi.org/10.1242/jcs.127381] [PMID: 23843607]
[36]
Chien W, Lee KL, Ding LW, et al. PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells. Br J Cancer 2013; 109(7): 1795-804.
[http://dx.doi.org/10.1038/bjc.2013.531] [PMID: 24002598]
[37]
Liu Q, Zhou B, Liao R, Zhou X, Yan X. PIAS4, upregulated in hepatocellular carcinoma, promotes tumorigenicity and metastasis. J Cell Biochem 2020; 121(5-6): 3372-81.
[http://dx.doi.org/10.1002/jcb.29610] [PMID: 31943317]
[38]
Shin EJ, Shin HM, Nam E, et al. DeSUMOylating isopeptidase: A second class of SUMO protease. EMBO Rep 2012; 13(4): 339-46.
[http://dx.doi.org/10.1038/embor.2012.3] [PMID: 22370726]
[39]
Shen HJ, Zhu HY, Yang C, Ji F. SENP2 regulates hepatocellular carcinoma cell growth by modulating the stability of β-catenin. Asian Pac J Cancer Prev 2012; 13(8): 3583-7.
[http://dx.doi.org/10.7314/APJCP.2012.13.8.3583] [PMID: 23098437]
[40]
Tan M, Gong H, Wang J, et al. SENP2 regulates MMP13 expression in a bladder cancer cell line through SUMOylation of TBL1/TBLR1. Sci Rep 2015; 5(1): 13996.
[http://dx.doi.org/10.1038/srep13996] [PMID: 26369384]

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