Pan-Cancer Analysis of CENPA as a Potential Prognostic and Immunological Biomarker in Human Cancer

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Abstract

Background: CENPA is a rare histone variant that regulates various active centromeres and neocentromeres via diverse signal pathways. However, the expression of CENPA correlated with the prognosis of patients in human pan-cancer is still largely underexplored.

Objective: To find the role of CENPA in the prognosis and immunotherapy of cancer patients.

Methods: In this study, multiple bioinformatic methods, including the ONCOMINE database, TCGA database, GEPIA database, DAVID database, and TIMER database were integrated to comprehensively investigate the prognosis and immunity of CENPA in pan-cancer.

Results: The results showed that CENPA was widely expressed in numerous cancer types, including liver cancer, lung cancer, bladder cancer, and gastric cancer. Meanwhile, the increased CENPA expression was significantly related with poor prognosis in breast cancer, lung cancer, and sarcoma. Additionally, CENPA expression had a positive coefficient for immune cell infiltration, including B cells, CD4+T cells, CD8+T cells, neutrophils, dendritic cells, and macrophages. Furthermore, we screened out TGCT, THCA, and LUSC as the most vital cancers correlated with CENPA expression in the immune microenvironment, according to immune score and stromal score. Notably, 47 common immune checkpoint genes were explored in 33 cancer types based on the coefficients of CENPA expression. In addition, CENPA expression was strongly associated with TMB and MSI in various cancers, like BLCA, BRCA, CESC, and CHOL. Moreover, there was a high correlation between CENPA expression and DNA methylation obtained by calculating relatedness coefficients. Enrichment analysis showed that CENPA might be involved in the progression of cancer through cell cycle-related pathways, p53 signaling pathways, and mismatch repair enrichment pathways.

Conclusion: Taken together, our results suggested that CEPNA could be considered a promising predictive biomarker affecting prognosis and immune infiltration in human pan-cancer.

Keywords: Bioinformatic analysis, CENPA, pan-cancer, cancer prognosis, immune infiltration, and systems biology

Graphical Abstract

[1]
Ali-Ahmad A. Sekulić N. CENP-A nucleosome-a chromatin-embedded pedestal for the centromere: Lessons learned from structural biology. Essays Biochem 2020; 64(2): 205-21.
[http://dx.doi.org/10.1042/EBC20190074] [PMID: 32720682]
[2]
Athwal RK, Walkiewicz MP, Baek S, et al. CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells. Epigenetics Chromatin 2015; 8(2): 2.
[http://dx.doi.org/10.1186/1756-8935-8-2] [PMID: 25788983]
[3]
Brimacombe CA, Burke JE, Parsa JY, et al. A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans. PLoS Biol 2019; 17(6): e3000331.
[http://dx.doi.org/10.1371/journal.pbio.3000331] [PMID: 31226107]
[4]
Dang HH, Ta HDK, Nguyen TTT, et al. Identifying GPSM family members as potential biomarkers in breast cancer: A comprehensive bioinformatics analysis. Biomedicines 2021; 9(9): 1144.
[http://dx.doi.org/10.3390/biomedicines9091144] [PMID: 34572330]
[5]
Cao R, Wang G, Qian K, et al. Silencing of HJURP induces dysregulation of cell cycle and ROS metabolism in bladder cancer cells via PPARγ-SIRT1 feedback loop. J Cancer 2017; 8(12): 2282-95.
[http://dx.doi.org/10.7150/jca.19967] [PMID: 28819432]
[6]
Chen CC, Mellone BG. Chromatin assembly: Journey to the center of the chromosome. J Cell Biol 2016; 214(1): 13-24.
[http://dx.doi.org/10.1083/jcb.201605005] [PMID: 27377247]
[7]
Lee K, Do TD, Nguyen-Trinh TD, Nguyen N, Trang N. Identification of gene expression signatures for psoriasis classification using machine learning techniques. OMICS 2020; 1: 100001.
[8]
Cui G, Geng L, Zhu L, et al. CFP is a prognostic biomarker and correlated with immune infiltrates in gastric cancer and lung cancer. J Cancer 2021; 12(11): 3378-90.
[http://dx.doi.org/10.7150/jca.50832] [PMID: 33976747]
[9]
Chen T, Huang H, Zhou Y, et al. HJURP promotes hepatocellular carcinoma proliferation by destabilizing p21 via the MAPK/ERK1/2 and AKT/GSK3β signaling pathways. J Exp Clin Cancer Res 2018; 37(1): 193.
[http://dx.doi.org/10.1186/s13046-018-0866-4] [PMID: 30111352]
[10]
Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 2017; 355(6322): eaaf8399.
[http://dx.doi.org/10.1126/science.aaf8399] [PMID: 28104840]
[11]
Fachinetti D, Logsdon GA, Abdullah A, Selzer EB, Cleveland DW, Black BE. CENP-A Modifications on Ser68 and Lys124 Are dispensable for establishment, maintenance, and long-term function of human centromeres. Dev Cell 2017; 40(1): 104-13.
[http://dx.doi.org/10.1016/j.devcel.2016.12.014] [PMID: 28073008]
[12]
Falk SJ, Lee J, Sekulic N, Sennett MA, Lee TH, Black BE. CENP-C directs a structural transition of CENP-A nucleosomes mainly through sliding of DNA gyres. Nat Struct Mol Biol 2016; 23(3): 204-8.
[http://dx.doi.org/10.1038/nsmb.3175] [PMID: 26878239]
[13]
Filipescu D, Naughtin M, Podsypanina K, et al. Essential role for centromeric factors following p53 loss and oncogenic transformation. Genes Dev 2017; 31(5): 463-80.
[http://dx.doi.org/10.1101/gad.290924.116] [PMID: 28356341]
[14]
Hoffmann S, Dumont M, Barra V, et al. CENP-A is dispensable for mitotic centromere function after initial centromere/kinetochore assembly. Cell Rep 2016; 17(9): 2394-404.
[http://dx.doi.org/10.1016/j.celrep.2016.10.084] [PMID: 27880912]
[15]
Hori T, Fukagawa T. Artificial generation of centromeres and kinetochores to understand their structure and function. Exp Cell Res 2020; 389(2): 111898.
[http://dx.doi.org/10.1016/j.yexcr.2020.111898] [PMID: 32035949]
[16]
Dai Y, Qiang W, Lin K, Gui Y, Lan X, Wang D. An immune-related gene signature for predicting survival and immunotherapy efficacy in hepatocellular carcinoma. Cancer Immunol Immunother 2021; 70(4): 967-79.
[http://dx.doi.org/10.1007/s00262-020-02743-0] [PMID: 33089373]
[17]
Huang W, Zhang H, Hao Y, et al. A non-synonymous single nucleotide polymorphism in the HJURP gene associated with susceptibility to hepatocellular carcinoma among Chinese. PLoS One 2016; 11(2): e0148618.
[http://dx.doi.org/10.1371/journal.pone.0148618] [PMID: 26863619]
[18]
Deng P, Zhou R, Zhang J, Cao L. Increased Expression of KNSTRN in Lung Adenocarcinoma Predicts Poor Prognosis: A Bioinformatics Analysis Based on TCGA Data. J Cancer 2021; 12(11): 3239-48.
[http://dx.doi.org/10.7150/jca.51591] [PMID: 33976733]
[19]
Fan Y, Liu B, Chen F, et al. Hepcidin upregulation in lung cancer: A potential therapeutic target associated with immune infiltration. Front Immunol 2021; 12: 612144.
[http://dx.doi.org/10.3389/fimmu.2021.612144] [PMID: 33868231]
[20]
Jeffries KA, Krupenko NI. Ceramide signaling and p53 pathways. Adv Cancer Res 2018; 140: 191-215.
[http://dx.doi.org/10.1016/bs.acr.2018.04.011] [PMID: 30060809]
[21]
Jeong JH, Yun JW, Kim HY, Heo CY, Lee S. Elucidation of novel therapeutic targets for breast cancer with ESR1-CCDC170 fusion. J Clin Med 2021; 10(4): 582.
[http://dx.doi.org/10.3390/jcm10040582] [PMID: 33557149]
[22]
Liu WT, Wang Y, Zhang J, et al. A novel strategy of integrated microarray analysis identifies CENPA, CDK1 and CDC20 as a cluster of diagnostic biomarkers in lung adenocarcinoma. Cancer Lett 2018; 425: 43-53.
[http://dx.doi.org/10.1016/j.canlet.2018.03.043] [PMID: 29608985]
[23]
Feng Y, Wang D, Xiong L, Zhen G, Tan J. Predictive value of RAD51 on the survival and drug responsiveness of ovarian cancer. Cancer Cell Int 2021; 21(1): 249.
[http://dx.doi.org/10.1186/s12935-021-01953-5] [PMID: 33952262]
[24]
Mahlke MA, Nechemia-Arbely Y. Guarding the Genome: CENP-A-Chromatin in Health and Cancer. Genes (Basel) 2020; 11(7): 810.
[http://dx.doi.org/10.3390/genes11070810] [PMID: 32708729]
[25]
Mlot C. Centromeres. A journey to the center of the chromosome. Science 2000; 290(5499): 2057-9.
[http://dx.doi.org/10.1126/science.290.5499.2057] [PMID: 11187825]
[26]
Nagpal H, Fierz B. The elusive structure of centro-chromatin: Molecular order or dynamic heterogenetity? J Mol Biol 2021; 433(6): 166676.
[http://dx.doi.org/10.1016/j.jmb.2020.10.010] [PMID: 33065112]
[27]
Nakano M, Okamoto Y, Ohzeki J, Masumoto H. Epigenetic assembly of centromeric chromatin at ectopic alpha-satellite sites on human chromosomes. J Cell Sci 2003; 116(Pt 19): 4021-34.
[http://dx.doi.org/10.1242/jcs.00697] [PMID: 12953060]
[28]
Huang X, Tang T, Wang X, Bai X, Liang T. Calreticulin couples with immune checkpoints in pancreatic cancer. Clin Transl Med 2020; 10(1): 36-44.
[http://dx.doi.org/10.1002/ctm2.10] [PMID: 32508042]
[29]
Lou W, Wang W, Chen J, Wang S, Huang Y. ncRNAs-mediated high expression of SEMA3F correlates with poor prognosis and tumor immune infiltration of hepatocellular carcinoma. Mol Ther Nucleic Acids 2021; 24(W1): 845-55.
[http://dx.doi.org/10.1016/j.omtn.2021.03.014] [PMID: 34026328]
[30]
Qu S, Liu J, Wang H. EVA1B to evaluate the tumor immune microenvironment and clinical prognosis in glioma. Front Immunol 2021; 12: 648416.
[http://dx.doi.org/10.3389/fimmu.2021.648416] [PMID: 33889156]
[31]
Niikura Y, Kitagawa R, Kitagawa K. CENP-A ubiquitylation contributes to maintaining the chromosomal location of the centromere. Molecules 2019; 24(3): 402.
[http://dx.doi.org/10.3390/molecules24030402] [PMID: 30678315]
[32]
Nye J, Melters DP, Dalal Y. The Art of War: Harnessing the epigenome against cancer. F1000research 2018; 7(F1000 Faculty Rev): 141.
[33]
O’Mara TA, Zhao M, Spurdle AB. Meta-analysis of gene expression studies in endometrial cancer identifies gene expression profiles associated with aggressive disease and patient outcome. Sci Rep 2016; 6(1): 36677.
[http://dx.doi.org/10.1038/srep36677] [PMID: 27830726]
[34]
Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 2018; 18(1): 33-50.
[http://dx.doi.org/10.1038/nrc.2017.96] [PMID: 29147025]
[35]
Prosée RF, Wenda JM, Steiner FA. Adaptations for centromere function in meiosis. Essays Biochem 2020; 64(2): 193-203.
[http://dx.doi.org/10.1042/EBC20190076] [PMID: 32406496]
[36]
Rosin LF, Mellone BG. Centromeres drive a hard bargain. Trends Genet 2017; 33(2): 101-17.
[http://dx.doi.org/10.1016/j.tig.2016.12.001] [PMID: 28069312]
[37]
Sharma AB, Dimitrov S, Hamiche A, Van Dyck E. Centromeric and ectopic assembly of CENP-A chromatin in health and cancer: Old marks and new tracks. Nucleic Acids Res 2019; 47(3): 1051-69.
[http://dx.doi.org/10.1093/nar/gky1298] [PMID: 30590707]
[38]
Shrestha RL, Ahn GS, Staples MI, et al. Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. Oncotarget 2017; 8(29): 46781-800.
[http://dx.doi.org/10.18632/oncotarget.18108] [PMID: 28596481]
[39]
Shukla M, Tong P, White SA, et al. Centromere DNA destabilizes H3 nucleosomes to promote CENP-A deposition during the cell cycle. Curr Biol 2018; 28(24): 3924-3936.e4.
[http://dx.doi.org/10.1016/j.cub.2018.10.049] [PMID: 30503616]
[40]
Srivastava S, Foltz DR. Posttranslational modifications of CENP-A: Marks of distinction. Chromosoma 2018; 127(3): 279-90.
[http://dx.doi.org/10.1007/s00412-018-0665-x] [PMID: 29569072]
[41]
Srivastava S. Zasadzińska E, Foltz DR. Posttranslational mechanisms controlling centromere function and assembly. Curr Opin Cell Biol 2018; 52: 126-35.
[http://dx.doi.org/10.1016/j.ceb.2018.03.003] [PMID: 29621654]
[42]
Stellfox ME, Bailey AO, Foltz DR. Putting CENP-A in its place. Cell Mol Life Sci 2013; 70(3): 387-406.
[http://dx.doi.org/10.1007/s00018-012-1048-8] [PMID: 22729156]
[43]
Sun X, Clermont PL, Jiao W, et al. Elevated expression of the centromere protein-A(CENP-A)-encoding gene as a prognostic and predictive biomarker in human cancers. Int J Cancer 2016; 139(4): 899-907.
[http://dx.doi.org/10.1002/ijc.30133] [PMID: 27062469]
[44]
Takada M, Zhang W, Suzuki A, et al. FBW7 loss promotes chromosomal instability and tumorigenesis via Cyclin E1/CDK2-mediated phosphorylation of CENP-A. Cancer Res 2017; 77(18): 4881-93.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-1240] [PMID: 28760857]
[45]
Taylor AM, Shih J, Ha G, et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 2018; 33(4): 676-689.e3.
[http://dx.doi.org/10.1016/j.ccell.2018.03.007] [PMID: 29622463]
[46]
Thul PJ, Åkesson L, Wiking M, et al. A subcellular map of the human proteome. Science 2017; 356(6340): eaal3321.
[http://dx.doi.org/10.1126/science.aal3321] [PMID: 28495876]
[47]
Umbreit NT, Zhang CZ, Lynch LD, et al. Mechanisms generating cancer genome complexity from a single cell division error. Science 2020; 368(6488): eaba0712.
[http://dx.doi.org/10.1126/science.aba0712] [PMID: 32299917]
[48]
Wang Y, Peng C, Cheng Z, et al. The prognostic significance of preoperative neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma receiving hepatectomy: A systematic review and meta-analysis. Int J Surg 2018; 55: 73-80.
[http://dx.doi.org/10.1016/j.ijsu.2018.05.022] [PMID: 29787804]
[49]
Zasadzińska E, Foltz DR. Orchestrating the specific assembly of centromeric nucleosomes. Prog Mol Subcell Biol 2017; 56: 165-92.
[http://dx.doi.org/10.1007/978-3-319-58592-5_7] [PMID: 28840237]
[50]
Zasadzińska E, Huang J, Bailey AO, et al. Inheritance of CENP-A Nucleosomes during DNA Replication Requires HJURP. Dev Cell 2018; 47(3): 348-362.e7.
[http://dx.doi.org/10.1016/j.devcel.2018.09.003] [PMID: 30293838]
[51]
Zhang L, Li Y, Liu W, Wang X, Tao Z. 5 Gleason score-associated gene signatures serve as novel biomarkers for identifying early recurring events and contributing to early diagnosis for Prostate Adenocarcinoma. J Cancer 2021; 12(12): 3626-47.
[http://dx.doi.org/10.7150/jca.52170] [PMID: 33995639]
[52]
Zhou BR, Yadav KNS, Borgnia M, et al. Atomic resolution cryo-EM structure of a native-like CENP-A nucleosome aided by an antibody fragment. Nat Commun 2019; 10(1): 2301.
[http://dx.doi.org/10.1038/s41467-019-10247-4] [PMID: 31127102]