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REVIEW

The roles and mechanisms of ETS1 in autoimmune diseases and cancers: A comprehensive review

Kai-Cheng Gao1,2† ,  Yu Zhao1,2† ,  Jie Jia1,2† ,  Dan Liang1,2 ,  Lin Xu1 ,  Yi-Qun Kuang1,2*
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1 Research Center for Clinical Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
2 Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming Medical University, Kunming, Yunnan, China
GPD 2023, 2(4), 2141 https://doi.org/10.36922/gpd.2141
Submitted: 30 October 2023 | Accepted: 14 December 2023 | Published: 26 December 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

E26 transformation-specific-1 (ETS1) is a founding member of the ETS transcription factor family. This transcription factor is highly conserved in amino acid sequences and highly expressed in many immune tissues, such as the thymus, spleen, and lymph gland. ETS1 plays multiple regulatory roles in immune-related diseases and acts as a transcriptional activator or inhibitor of many genes to regulate immune cell differentiation, development, apoptosis, and tumor occurrence. The expression level of ETS1 is correlated with disease severity. However, the molecular mechanisms behind disease and tumor progression mediated by ETS1 have not been fully elucidated. In addition, the therapeutic potential of ETS1 in clinical treatment remains to be further explored. Here, we review and summarize the molecular structure and functions of ETS1 and then focus on the roles of ETS1 in the occurrence of autoimmune diseases and cancers. This review provides a reference corroborating ETS1 as a potential therapeutic target for immune-related diseases and cancers.

Keywords
ETS1
Autoimmune diseases
Cancer
Immunity
Funding
National Natural Science Foundation of China
Joint Special Fund of the Department of Science and Technology, Yunnan Province – Kunming Medical University
Yunnan Fundamental Research Projects
Fund of Beijing Key Laboratory for HIV/AIDS Research
Conflict of interest
The authors have no personal, financial, or institutional interest with regard to any of the drugs, materials, or devices described in this article.
References
  1. Wang Y, Huang Z, Sun M, et al., 2023, ETS transcription factors: Multifaceted players from cancer progression to tumor immunity. Biochim Biophys Acta Rev Cancer, 1878(3): 188872. https://doi.org/10.1016/j.bbcan.2023.188872

 

  1. Garrett-Sinha LA, 2013, Review of Ets1 structure, function, and roles in immunity. Cell Mol Life Sci, 70(18): 3375–3390. https://doi.org/10.1007/s00018-012-1243-7

 

  1. Fry EA, Mallakin A, Inoue K, 2018, Translocations involving ETS family proteins in human cancer. Integr Cancer Sci Ther, 5(4): 10.15761/ICST.1000281. https://doi.org/10.15761/ICST.1000281

 

  1. He YS, Yang XK, Hu YQ, et al., 2021, Emerging role of Fli1 in autoimmune diseases. Int Immunopharmacol, 90: 107127. https://doi.org/10.1016/j.intimp.2020.107127

 

  1. Garrett-Sinha LA, 2023, An update on the roles of transcription factor Ets1 in autoimmune diseases. WIREs Mech Dis, 15(6): e1627. https://doi.org/10.1002/wsbm.1627

 

  1. Wang C, Kam RK, Shi W, et al., 2015, The Proto-oncogene transcription factor Ets1 regulates neural crest development through histone deacetylase 1 to mediate output of bone morphogenetic protein signaling. J Biol Chem, 290(36): 21925–21938. https://doi.org/10.1074/jbc.M115.644864

 

  1. Piserchio A, Warthaka M, Kaoud TS, et al., 2017, Local destabilization, rigid body, and fuzzy docking facilitate the phosphorylation of the transcription factor Ets-1 by the mitogen-activated protein kinase ERK2. Proc Natl Acad Sci U S A, 114(31): E6287–E6296. https://doi.org/10.1073/pnas.1702973114

 

  1. Higuchi T, Bartel FO, Masuya M, et al., 2007, Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice. Mol Cell Biol, 27(9): 3353–3366. https://doi.org/10.1128/MCB.01871-06

 

  1. Dittmer J, 2015, The role of the transcription factor Ets1 in carcinoma. Semin Cancer Biol, 35: 20–38. https://doi.org/10.1016/j.semcancer.2015.09.010

 

  1. Sizemore GM, Pitarresi JR, Balakrishnan S, et al., 2017, The ETS family of oncogenic transcription factors in solid tumours. Nat Rev Cancer, 17(6): 337–351. https://doi.org/10.1038/nrc.2017.20

 

  1. Huang K, Xhani S, Albrecht AV, et al., 2019, Mechanism of cognate sequence discrimination by the ETS-family transcription factor ETS-1. J Biol Chem, 294(25): 9666–9978. https://doi.org/10.1074/jbc.RA119.007866

 

  1. Skalicky JJ, Donaldson LW, Petersen JM, et al., 1996, Structural coupling of the inhibitory regions flanking the ETS domain of murine Ets-1. Protein Sci, 5(2): 296–309. https://doi.org/10.1002/pro.5560050214

 

  1. Donaldson LW, Petersen JM, Graves BJ, et al., 1996, Solution structure of the ETS domain from murine Ets-1: a winged helix-turn-helix DNA binding motif. EMBO J, 15(1): 125–134. https://doi.org/10.1002/j.1460-2075.1996.tb00340.x

 

  1. Karolak A, van der Vaart A, 2012, Importance of local interactions for the stability of inhibitory helix 1 in apo Ets- 1. Biophys Chem, 165–166: 74–78. https://doi.org/10.1016/j.bpc.2012.03.007

 

  1. Han JW, Zheng HF, Cui Y, et al., 2009, Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet, 41(11): 1234–1237. https://doi.org/10.1038/ng.472

 

  1. Yang W, Shen N, Ye DQ, et al., 2010, Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet, 6(2): e1000841. https://doi.org/10.1371/journal.pgen.1000841

 

  1. Zhong J, Ding R, Jiang H, et al., 2022, Single-cell RNA sequencing reveals the molecular features of peripheral blood immune cells in children, adults and centenarians. Front Immunol, 13: 1081889. https://doi.org/10.3389/fimmu.2022.1081889

 

  1. Zhang J, Zhang Y, Zhang L, et al., 2013, Epistatic interaction between genetic variants in susceptibility gene ETS1 correlates with IL-17 levels in SLE patients. Ann Hum Genet, 77(4): 344–350. https://doi.org/10.1111/ahg.12018

 

  1. John SA, Clements JL, Russell LM, et al., 2008, Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. J Biol Chem, 283(2): 951–962. https://doi.org/10.1074/jbc.M705262200

 

  1. Jin L, Fang X, Dai C, et al., 2019, The potential role of Ets-1 and miR-326 in CD19(+)B cells in the pathogenesis of patients with systemic lupus erythematosus. Clin Rheumatol, 38(4): 1031–1038. https://doi.org/10.1007/s10067-018-4371-0

 

  1. Moisan J, Grenningloh R, Bettelli E, et al., 2007, Ets-1 is a negative regulator of Th17 differentiation. J Exp Med, 204(12): 2825–2835. https://doi.org/10.1084/jem.20070994

 

  1. Na SY, Park MJ, Park S, et al., 2016, MicroRNA-155 regulates the Th17 immune response by targeting Ets-1 in Behcet’s disease. Clin Exp Rheumatol, 34(6 Suppl 102): S56–S63.

 

  1. Luo W, Mayeux J, Gutierrez T, et al., 2014, A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol, 193(2): 909–920. https://doi.org/10.4049/jimmunol.1400666

 

  1. Kim CJ, Lee CG, Jung JY, et al., 2018, The transcription factor Ets1 suppresses T follicular helper type 2 cell differentiation to halt the onset of systemic lupus erythematosus. Immunity, 49(6): 1034–1048.e8. https://doi.org/10.1016/j.immuni.2018.10.012

 

  1. Sunshine A, Goich D, Stith A, et al., 2019, Ets1 controls the development of B cell autoimmune responses in a cell-intrinsic manner. Immunohorizons, 3(7): 331–340. https://doi.org/10.4049/immunohorizons.1900033

 

  1. Xia Y, Tao JH, Fang X, et al., 2018, MicroRNA-326 upregulates B cell activity and autoantibody production in lupus disease of MRL/lpr mice. Mol Ther Nucleic Acids, 11: 284–291. https://doi.org/10.1016/j.omtn.2018.02.010

 

  1. Chen L, Huang Z, Yang B, et al., 2015, Association of E26 transformation specific sequence 1 variants with rheumatoid arthritis in Chinese han population. PLoS One, 10(8): e0134875. https://doi.org/10.1371/journal.pone.0134875

 

  1. Yang B, Luo L, Chen L, et al., 2021, ETS1 polymorphism rs73013527 in relation to serum RANKL levels among patients with RA. Medicine (Baltimore), 100(5): e24562. https://doi.org/10.1097/MD.0000000000024562

 

  1. Yan M, Komatsu N, Muro R, et al., 2022, ETS1 is a key transcription factor that drives RANKL-expressing, tissue-destructive fibroblasts. Nat Immunol, 23(9): 1303–1304. https://doi.org/10.1038/s41590-022-01298-9

 

  1. Zhao N, Zou H, Qin J, et al., 2018, MicroRNA-326 contributes to autoimmune thyroiditis by targeting the Ets-1 protein. Endocrine, 59(1): 120–129. https://doi.org/10.1007/s12020-017-1465-4

 

  1. Zhao N, Wang Z, Cui X, et al., 2021, In vivo inhibition of MicroRNA-326 in a NOD.H-2(h4) mouse model of autoimmune thyroiditis. Front Immunol, 12: 620916. https://doi.org/10.3389/fimmu.2021.620916

 

  1. Li L, Ma X, Zhao YF, et al., 2020, MiR-1-3p facilitates Th17 differentiation associating with multiple sclerosis via targeting ETS1. Eur Rev Med Pharmacol Sci, 24(12): 6881–6892. https://doi.org/10.26355/eurrev_202006_21678

 

  1. Luo Y, Yang H, Wan Y, et al., 2022, Endothelial ETS1 inhibition exacerbate blood-brain barrier dysfunction in multiple sclerosis through inducing endothelial-to-mesenchymal transition. Cell Death Dis, 13(5): 462. https://doi.org/10.1038/s41419-022-04888-5

 

  1. Buggy Y, Maguire TM, McGreal G, et al., 2004, Overexpression of the Ets-1 transcription factor in human breast cancer. Br J Cancer, 91(7): 1308–1315. https://doi.org/10.1038/sj.bjc.6602128

 

  1. Li Y, Wu T, Peng Z, et al., 2022, ETS1 is a prognostic biomarker of triple-negative breast cancer and promotes the triple-negative breast cancer progression through the YAP signaling. Am J Cancer Res, 12(11): 5074–5084.

 

  1. Fang LW, Kao YH, Chuang YT, et al., 2019, Ets-1 enhances tumor migration through regulation of CCR7 expression. BMB Rep, 52(9): 548–553. https://doi.org/10.5483/BMBRep.2019.52.9.232

 

  1. Peng P, Ren Y, Wan F, et al., 2023, Sculponeatin A promotes the ETS1-SYVN1 interaction to induce SLC7A11/xCT-dependent ferroptosis in breast cancer. Phytomedicine, 117: 154921. https://doi.org/10.1016/j.phymed.2023.154921

 

  1. Furlan A, Vercamer C, Heliot L, et al., 2019, Ets-1 drives breast cancer cell angiogenic potential and interactions between breast cancer and endothelial cells. Int J Oncol, 54(1): 29–40. https://doi.org/10.3892/ijo.2018.4605

 

  1. Ballschmieter P, Braig M, Lindemann RK, et al., 2003, Splicing variant DeltaVII-Ets1 is downregulated in invasive Ets1- expressing breast cancer cells. Int J Oncol, 22(4): 849–853. https://doi.org/10.3892/ijo.22.4.849

 

  1. Furlan A, Vercamer C, Bouali F, et al., 2014, Ets-1 controls breast cancer cell balance between invasion and growth. Int J Cancer, 135(10): 2317–2328. https://doi.org/10.1002/ijc.28881

 

  1. Kim GC, Lee CG, Verma R, et al., 2020, ETS1 suppresses tumorigenesis of human breast cancer via trans-activation of canonical tumor suppressor genes. Front Oncol, 10: 642. https://doi.org/10.3389/fonc.2020.00642

 

  1. Nazir SU, Kumar R, Singh A, et al., 2019, Breast cancer invasion and progression by MMP-9 through Ets-1 transcription factor. Gene, 711: 143952. https://doi.org/10.1016/j.gene.2019.143952

 

  1. Ito H, Duxbury M, Benoit E, et al., 2004, Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1- dependent induction of matrix metalloproteinase-2. Cancer Res, 64(20): 7439–7446. https://doi.org/10.1158/0008-5472.CAN-04-1177

 

  1. Gao H, Peng C, Liang B, et al., 2014, beta6 integrin induces the expression of metalloproteinase-3 and metalloproteinase-9 in colon cancer cells via ERK-ETS1 pathway. Cancer Lett, 354(2): 427–437. https://doi.org/10.1016/j.canlet.2014.08.017

 

  1. Tsai CL, Jung SM, Chi LM, et al., 2021, Glycogen synthase kinase-3 beta (GSK3beta)-mediated phosphorylation of ETS1 promotes progression of ovarian carcinoma. Aging (Albany NY), 13(10): 13739–13763. https://doi.org/10.18632/aging.202966

 

  1. Phuchareon J, McCormick F, Eisele DW, et al., 2015, EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function. Proc Natl Acad Sci U S A, 112(29): E3855–E3863. https://doi.org/10.1073/pnas.1510733112

 

  1. Seidel JJ, Graves BJ, 2002, An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors. Genes Dev, 16(1): 127–137. https://doi.org/10.1101/gad.950902

 

  1. Myers E, Hill AD, Kelly G, et al., 2005, Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer. Clin Cancer Res, 11(6): 2111–2122. https://doi.org/10.1158/1078-0432.CCR-04-1192

 

  1. Tomar S, Plotnik JP, Haley J, et al., 2018, ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase. Cancer Lett, 414: 190–204. https://doi.org/10.1016/j.canlet.2017.11.012

 

  1. Ning S, Chao HJ, Li S, et al., 2022, The auto-inhibition mechanism of transcription factor Ets-1 induced by phosphorylation on the intrinsically disordered region. Comput Struct Biotechnol J, 20: 1132–1141. https://doi.org/10.1016/j.csbj.2022.02.025

 

  1. Wei W, Hu Z, Fu H, et al., 2012, MicroRNA-1 and microRNA-499 downregulate the expression of the ets1 proto-oncogene in HepG2 cells. Oncol Rep, 28(2): 701–706. https://doi.org/10.3892/or.2012.1850

 

  1. Ma N, Chen F, Shen SL, et al., 2015, MicroRNA-129-5p inhibits hepatocellular carcinoma cell metastasis and invasion via targeting ETS1. Biochem Biophys Res Commun, 461(4): 618–623. https://doi.org/10.1016/j.bbrc.2015.04.075

 

  1. Xu C, Liu S, Fu H, et al., 2010, MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells. Eur J Cancer, 46(15): 2828– 2836. https://doi.org/10.1016/j.ejca.2010.06.127

 

  1. Allam MM, Diab KA, Khalil FO, et al., 2022, The association between micro-RNA gene polymorphisms and the development of hepatocellular carcinoma in Egyptian patients. Arch Med Sci, 18(1): 62–70. https://doi.org/10.5114/aoms/100600

 

  1. Zheng L, Qi T, Yang D, et al., 2013, microRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS One, 8(1): e55719. https://doi.org/10.1371/journal.pone.0055719

 

  1. Zheng L, Pu J, Qi T, et al., 2013, miRNA-145 targets v-ets erythroblastosis virus E26 oncogene homolog 1 to suppress the invasion, metastasis, and angiogenesis of gastric cancer cells. Mol Cancer Res, 11(2): 182–193. https://doi.org/10.1158/1541-7786.MCR-12-0534

 

  1. Zhang Y, Yan LX, Wu QN, et al., 2011, miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res, 71(10): 3552–3562. https://doi.org/10.1158/0008-5472.CAN-10-2435

 

  1. Li W, Zang W, Liu P, et al., 2014, MicroRNA-124 inhibits cellular proliferation and invasion by targeting Ets-1 in breast cancer. Tumour Biol, 35(11): 10897–10904. https://doi.org/10.1007/s13277-014-2402-2

 

  1. Wang R, Ma Y, Yu D, et al., 2015, miR-377 functions as a tumor suppressor in human clear cell renal cell carcinoma by targeting ETS1. Biomed Pharmacother, 70: 64–71. https://doi.org/10.1016/j.biopha.2015.01.012

 

  1. Hua S, Lei L, Deng L, et al., 2018, miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1. Oncogene, 37(12): 1624–1636. https://doi.org/10.1038/s41388-017-0057-3

 

  1. Zhai W, Ma J, Zhu R, et al., 2018, MiR-532-5p suppresses renal cancer cell proliferation by disrupting the ETS1- mediated positive feedback loop with the KRAS-NAP1L1/P-ERK axis. Br J Cancer, 119(5): 591–604. https://doi.org/10.1038/s41416-018-0196-5

 

  1. Jin L, Huang S, Guan C, et al., 2020, ETS1-activated SNHG10 exerts oncogenic functions in glioma via targeting miR-532-3p/FBXL19 axis. Cancer Cell Int, 20(1): 589. https://doi.org/10.1186/s12935-020-01649-2

 

  1. Bukavina L, Bensalah K, Bray F, et al., 2022, Epidemiology of renal cell carcinoma: 2022 update. Eur Urol, 82(5): 529–542. https://doi.org/10.1016/j.eururo.2022.08.019

 

  1. Yang X, Zhang Y, Fan H, 2021, Downregulation of SBF2-AS1 functions as a tumor suppressor in clear cell renal cell carcinoma by inhibiting miR-338-3p-targeted ETS1. Cancer Gene Ther, 28(7–8): 813–827. https://doi.org/10.1038/s41417-020-0197-4

 

  1. Pan G, Zhang J, You F, et al., 2022, ETS proto-oncogene 1-activated muskelin 1 antisense RNA drives the malignant progression of hepatocellular carcinoma by targeting miR- 22-3p to upregulate ETS Proto-Oncogene 1. Bioengineered, 13(1): 1346–1358. https://doi.org/10.1080/21655979.2021.2017565

 

  1. Sun Y, Zhang H, Ma R, et al., 2023, ETS-1-activated LINC01016 over-expression promotes tumor progression via suppression of RFFL-mediated DHX9 ubiquitination degradation in breast cancers. Cell Death Dis, 14(8): 507. https://doi.org/10.1038/s41419-023-06016-3

 

  1. Vallarelli AF, Rachakonda PS, Andre J, et al., 2016, TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation. Oncotarget, 7(33): 53127–53136. https://doi.org/10.18632/oncotarget.10634

 

  1. Li Y, Zhou QL, Sun W, et al., 2015, Non-canonical NF-kappaB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat Cell Biol, 17(10): 1327–1338. https://doi.org/10.1038/ncb3240

 

  1. Kohli JS, Mir H, Wasif A, et al., 2017, ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression. Oncotarget, 8(61): 104408–104417. https://doi.org/10.18632/oncotarget.22254

 

  1. Xu X, Li Y, Bharath SR, et al., 2018, Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1. Nat Commun, 9(1): 3183. https://doi.org/10.1038/s41467-018-05644-0

 

  1. Gabler L, Lotsch D, Kirchhofer D, et al., 2019, TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAF(V600E)/TERT promoter double-mutated glioma. Acta Neuropathol Commun, 7(1): 128. https://doi.org/10.1186/s40478-019-0775-6

 

  1. Dittmer J, 2003, The biology of the Ets1 proto-oncogene. Mol Cancer, 2: 29. https://doi.org/10.1186/1476-4598-2-29

 

  1. Priebe V, Sartori G, Napoli S, et al., 2020, Role of ETS1 in the transcriptional network of diffuse large B cell lymphoma of the activated B cell-like type. Cancers (Basel), 12(7): 1912. https://doi.org/10.3390/cancers12071912

 

  1. Overbeck BM, Martin-Subero JI, Ammerpohl O, et al., 2012, ETS1 encoding a transcription factor involved in B-cell differentiation is recurrently deleted and down-regulated in classical Hodgkin’s lymphoma. Haematologica, 97(10): 1612–1614. https://doi.org/10.3324/haematol.2012.061770

 

  1. Bonetti P, Testoni M, Scandurra M, et al., 2013, Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma. Blood, 122(13): 2233–2241. https://doi.org/10.1182/blood-2013-01-475772

 

  1. Chung EYL, Sartori G, Ponzoni M, et al., 2023, ETS1 phosphorylation at threonine 38 is associated with the cell of origin of diffuse large B cell lymphoma and sustains the growth of tumour cells. Br J Haematol, 203(2): 244–254. https://doi.org/10.1111/bjh.19018

 

  1. McCarter AC, Della Gatta G, Melnick A, et al., 2020, Combinatorial ETS1-dependent control of oncogenic NOTCH1 enhancers in T-cell leukemia. Blood Cancer Discov, 1(2): 178–197. https://doi.org/10.1158/2643-3230.BCD-20-0026

 

  1. Luchtel RA, Zhao Y, Aggarwal RK, et al., 2022, ETS1 is a novel transcriptional regulator of adult T-cell leukemia/ lymphoma of North American descent. Blood Adv, 6(20): 5613–5624. https://doi.org/10.1182/bloodadvances.2022007725
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