The epithelial-to-mesenchymal transition (EMT) is a complex cellular process in which epithelial cells acquire mesenchymal properties. EMT occurs in three biological settings: development, wound healing and fibrosis, and tumor progression. Despite occurring in three independent biological settings, EMT signaling shares some molecular mechanisms that allow epithelial cells to de-differentiate and acquire mesenchymal characteristics that confer cells invasive and migratory capacity to distant sites. Here we summarize the molecular mechanism that delineates EMT and we will focus on the role of E2 promoter binding factors (E2Fs) in EMT during tumor progression. Since the E2Fs are presently undruggable due to their control in numerous pivotal cellular functions and due to the lack of selectivity against individual E2Fs, we will also discuss the role of three mitotic regulators and/or mitotic kinases controlled by the E2Fs (NEK2, Mps1/TTK, and SGO1) in EMT that can be useful as drug targets.
Impact statement
The study of the epithelial to mesenchymal transition (EMT) is an active area of research since it is one of the early intermediates to invasion and metastasis—a state of the cancer cells that ultimately kills many cancer patients. We will present in this review that besides their canonical roles as regulators of proliferation, unregulated expression of the E2F transcription factors may contribute to cancer initiation and progression to metastasis by signaling centrosome amplification, chromosome instability, and EMT. Since our discovery that the E2F activators control centrosome amplification and mitosis in cancer cells, we have identified centrosome and mitotic regulators that may represent actionable targets against EMT and metastasis in cancer cells. This is impactful to all of the cancer patients in which the Cdk/Rb/E2F pathway is deregulated, which has been estimated to be most cancer patients with solid tumors.
YilmazMChristoforiG.EMT, the cytoskeleton, and cancer cell invasion.Cancer Metastasis Rev2009;
28:15–33
9.
NisticoPBissellMJRadiskyDC.Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases.Cold Spring Harb Perspect Biol2012;
4:pii: a011908
10.
Barrallo-GimenoANietoMA.The Snail genes as inducers of cell movement and survival: implications in development and cancer.Development2005;
132:3151–61
11.
De CraeneBBerxG.Regulatory networks defining EMT during cancer initiation and progression.Nature Rev Cancer2013;
13:97–110
12.
XuJLamouilleSDerynckR.TGF-beta-induced epithelial to mesenchymal transition.Cell Res2009;
19:156–72
13.
KalluriRWeinbergRA.The basics of epithelial-mesenchymal transition.J Clin Invest2009;
119:1420–8
14.
WangYZhouBP.Epithelial-mesenchymal transition – a hallmark of breast cancer metastasis.Cancer Hallm2013;
1:38–49
15.
CreightonCJGibbonsDLKurieJM.The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective. Cancer Manag Res2013;
5:187–95
16.
PastushenkoIBlanpainC.EMT transition states during tumor progression and metastasis.Trends Cell Biol2019;
29:212–26
17.
LammensTLiJLeoneGDe VeylderL.Atypical E2Fs: new players in the E2F transcription factor family. Trends Cell Biol2009;
19:111–8
18.
HiebertSWChellappanSPHorowitzJMNevinsJR.The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F.Genes Dev1992;
6:177–85
19.
ArroyoMRaychaudhuriP.Retinoblastoma-repression of E2F-dependent transcription depends on the ability of the retinoblastoma protein to interact with E2F and is abrogated by the adenovirus E1A oncoprotein.Nucl Acids Res1992;
20:5947–54
20.
QinXQChittendenTLivingstonDMKaelinWGJr.Identification of a growth suppression domain within the retinoblastoma gene product.Genes Dev1992;
6:953–64
21.
WeintraubSJPraterCADeanDC.Retinoblastoma protein switches the E2F site from positive to negative element.Nature1992;
358:259–61
22.
ChellappanSPHiebertSMudryjMHorowitzJMNevinsJR.The E2F transcription factor is a cellular target for the RB protein.Cell1991;
65:1053–61
23.
ChittendenTLivingstonDMKaelinWGJr.RB associates with an E2F-like, sequence-specific DNA-binding protein.Cold Spring Harb Symp Quant Biol1991;
56:187–95
24.
BagchiSWeinmannRRaychaudhuriP.The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.Cell1991;
65:1063–72
25.
IaquintaPJLeesJA.Life and death decisions by the E2F transcription factors.Curr Opin Cell Biol2007;
19:649–57
26.
AttwoollCLazzerini DenchiEHelinK.The E2F family: specific functions and overlapping interests. EMBO J2004;
23:4709–16
27.
TrimarchiJMLeesJA.Sibling rivalry in the E2F family.Nat Rev Mol Cell Biol2002;
3:11–20
28.
ChenHZTsaiSYLeoneG.Emerging roles of E2Fs in cancer: an exit from cell cycle control.Nat Rev Cancer2009;
9:785–97
29.
CamHDynlachtBD.Emerging roles for E2F: beyond the G1/S transition and DNA replication.Cancer Cell2003;
3:311–6
30.
DeGregoriJ.The genetics of the E2F family of transcription factors: shared functions and unique roles.Biochim Biophys Acta2002;
1602:131–50
31.
StevauxODysonNJ.A revised picture of the E2F transcriptional network and RB function.Curr Opin Cell Biol2002;
14:684–91
32.
SaavedraHIWuLde BruinATimmersCRosolTJWeinsteinMRobinsonMLLeoneG.Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb. Cell Growth Differ2002;
13:215–25
33.
ShanBLeeWH.Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis.Mol Cell Biol1994;
14:8166–73
34.
HuangYLNingGChenLBLianYFGuYRWangJLChenDMWeiHHuangYH.Promising diagnostic and prognostic value of E2Fs in human hepatocellular carcinoma.Cancer Manag Res2019;
11:1725–40
35.
LeeMRivera-RiveraYMorenoCSSaavedraHI.The E2F activators control multiple mitotic regulators and maintain genomic integrity through Sgo1 and BubR1.Oncotarget2017;
8:77649–72
36.
LiuZLBiXWLiuPPLeiDXWangYLiZMJiangWQXiaY.Expressions and prognostic values of the E2F transcription factors in human breast carcinoma. Cancer Manag Res2018;
10:3521–32
37.
LiYHuangJYangDXiangSSunJLiHRenG.Expression patterns of E2F transcription factors and their potential prognostic roles in breast cancer.Oncol Lett2018;
15:9216–30
38.
ZieboldULeeEYBronsonRTLeesJA.E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas.Mol Cell Biol2003;
23:6542–52
39.
YamasakiLBronsonRWilliamsBODysonNJHarlowEJacksT.Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−) mice.Nat Genet1998;
18:360–4
40.
PierceAMSchneider-BroussardRGimenez-ContiIBRussellJLContiCJJohnsonDG.E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model.Mol Cell Biol1999;
19:6408–14
41.
WuLde BruinAWangHSimmonsTCleghornWGoldenbergLESitesESandyATrimboliAFernandezSAEngCShapiroCLeoneG.Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis.Oncogene2015;
34:119–28
42.
AndrechekER.HER2/Neu tumorigenesis and metastasis is regulated by E2F activator transcription factors.Oncogene2015;
34:217–25
43.
YuwanitaIBarnesDMontereyMDO'ReillySAndrechekER.Increased metastasis with loss of E2F2 in Myc-driven tumors.Oncotarget2015;
6:38210–24
44.
SaavedraHIMaitiBTimmersCAlturaRTokuyamaYFukasawaKLeoneG.Inactivation of E2F3 results in centrosome amplification.Cancer Cell2003;
3:333–46
45.
LeeMOprea-IliesGSaavedraHI.Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis.Oncotarget2015;
6:37316–34
46.
LeeMYMorenoCSSaavedraHI.E2F activators signal and maintain centrosome amplification in breast cancer cells.Mol Cell Biol2014;
34:2581–99
47.
AdonAMZengXHarrisonMKSannemSKiyokawaHKaldisPSaavedraHI.Cdk2 and Cdk4 regulate the centrosome cycle and are critical mediators of centrosome amplification in p53-null cells.Mol Cell Biol2010;
30:694–710
48.
LevineMSBakkerBBoeckxBMoyettJLuJVitreBSpieringsDCLansdorpPMClevelandDWLambrechtsDFoijerFHollandAJ.Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals.Dev Cell2017;
40:313–22.e5
49.
GodinhoSAPellmanD.Causes and consequences of centrosome abnormalities in cancer.Philos Trans R Soc Lond B Biol Sci2014;
369:20130467
50.
OkudaMHornHFTaraporePTokuyamaYSmulianAGChanPKKnudsenESHofmannIASnyderJDBoveKEFukasawaK.Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication.Cell2000;
103:127–40
51.
DzhindzhevNSTzolovskyGLipinszkiZAbdelazizMDebskiJDadlezMGloverDM.Two-step phosphorylation of Ana2 by Plk4 is required for the sequential loading of Ana2 and Sas6 to initiate procentriole formation.Open Biol2017;
7:170247
52.
VulprechtJDavidATibeliusACastielAKonotopGLiuFBestvaterFRaabMSZentgrafHIzraeliSKramerA.STIL is required for centriole duplication in human cells.J Cell Sci2012;
125:1353–62
53.
ArquintCCubizollesFMorandASchmidtANiggEA.The SKP1-Cullin-F-box E3 ligase betaTrCP and CDK2 cooperate to control STIL abundance and centriole number.Open Biol2018;
8:pii:170-523
54.
TokuyamaYHornHFKawamuraKTaraporePFukasawaK.Specific phosphorylation of nucleophosmin on Thr(199) by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication.J Biol Chem2001;
276:21529–37
55.
McLamarrahTABusterDWGallettaBJBoeseCJRyniawecJMHollingsworthNAByrnesAEBrownleeCWSlepKCRusanNMRogersGC.An ordered pattern of Ana2 phosphorylation by Plk4 is required for centriole assembly.J Cell Biol2018;
217:1217–31
56.
DenuRAZasadilLMKanughCLaffinJWeaverBABurkardME.Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer.BMC Cancer2016;
16:47
57.
JusinoSFernandez-PadinFMSaavedraHI.Centrosome aberrations and chromosome instability contribute to tumorigenesis and intra-tumor heterogeneity.J Cancer Metastasis Treat2018;
4:pii:43
58.
GodinhoSAPiconeRBuruteMDagherRSuYLeungCTPolyakKBruggeJSTheryMPellmanD.Oncogene-like induction of cellular invasion from centrosome amplification.Nature2014;
510:167–71
59.
LeeMOprea-IliesGSaavedraHI.Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis.Oncotarget2015;
6:37316–34
60.
SchaalCPillaiSChellappanSP.The Rb-E2F transcriptional regulatory pathway in tumor angiogenesis and metastasis. Adv Cancer Res2014;
121:147–82
61.
ZhangSYLiuSCJohnsonDGKlein-SzantoAJ.E2F-1 gene transfer enhances invasiveness of human head and neck carcinoma cell lines.Cancer Res2000;
60:5972–6
62.
JohnsonJLPillaiSPernazzaDSebtiSMLawrenceNJChellappanSP.Regulation of matrix metalloproteinase genes by E2F transcription factors: Rb-Raf-1 interaction as a novel target for metastatic disease.Cancer Res2012;
72:516–26
63.
LuZNianZJingjingZTaoLQuanL.MicroRNA-424/E2F6 feedback loop modulates cell invasion, migration and EMT in endometrial carcinoma.Oncotarget2017;
8:114281–91
64.
YeYYMeiJWXiangSSLiHFMaQSongXLWangZZhangYCLiuYCJinYPHuYPJiangLLiuFTZhangYJHaoYJLiuYB.MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7.Cell Death Dis2018;
9:410
65.
PillaiSTrevinoJRawalBSinghSKovacsMLiXSchellMHauraEBeplerGChellappanS.beta-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition.Cancer Res2015;
75:1009–20
66.
KhanFMMarquardtSGuptaSKKnollSSchmitzUSpitschakAEngelmannDVeraJWolkenhauerOPutzerBM.Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures.Nat Commun2017;
8:198
67.
WangTChenXQiaoWKongLSunDLiZ.Transcription factor E2F1 promotes EMT by regulating ZEB2 in small cell lung cancer.BMC Cancer2017;
17:719
68.
LiZGuoYJiangHZhangTJinCYoungCYYuanH.Differential regulation of MMPs by E2F1, Sp1 and NF-kappa B controls the small cell lung cancer invasive phenotype.BMC Cancer2014;
14:276
69.
ChenJGongCMaoHLiZFangZChenQLinMJiangXHuYWangWZhangXChenXLiH.E2F1/SP3/STAT6 axis is required for IL-4-induced epithelial-mesenchymal transition of colorectal cancer cells.Int J Oncol2018;
53:567–78
70.
WangZSunXBaoYMoJDuHHuJZhangX.E2F1 silencing inhibits migration and invasion of osteosarcoma cells via regulating DDR1 expression.Int J Oncol2017;
51:1639–50
71.
LiangYXLuJMMoRJHeHCXieJJiangFNLinZYChenYRWuYDLuoHWLuoZZhongWD.E2F1 promotes tumor cell invasion and migration through regulating CD147 in prostate cancer.Int J Oncol2016;
48:1650–8
72.
KnollSFurstKKowtharapuBSchmitzUMarquardtSWolkenhauerOMartinHPutzerBM.E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation.EMBO Rep2014;
15:1315–29
73.
FelicianoAGarcia-MayeaYJubierreLMirCHummelMCastellviJHernandez-LosaJPaciucciRSansanoISunYRamonYCSKondonHSorianoASeguraMLyakhovichAMELL.miR-99a reveals two novel oncogenic proteins E2F2 and EMR2 and represses stemness in lung cancer.Cell Death Dis2017;
8:e3141
74.
YeJZhangWLiuSLiuYLiuK.miR-363 inhibits the growth, migration and invasion of hepatocellular carcinoma cells by regulating E2F3.Oncol Rep2017;
38:3677–84
75.
LiuLQiuMTanGLiangZQinYChenLChenHLiuJ.miR-200c inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3.J Transl Med2014;
12:305
76.
RuckertFJoenssonPSaegerHDGrutzmannRPilarskyC.Functional analysis of LOXL2 in pancreatic carcinoma.Int J Colorectal Dis2010;
25:303–11
77.
HollernDPHoneysettJCardiffRDAndrechekER.The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer.Mol Cell Biol2014;
34:3229–43
78.
BaizDDapasBFarraRScaggianteBPozzatoGZanconatiFFiottiNConsoloniLChiarettiSGrassiG.Bortezomib effect on E2F and cyclin family members in human hepatocellular carcinoma cell lines.World J Gastroenterol2014;
20:795–803
79.
XieLLawBKAakreMEEdgertonMShyrYBhowmickNAMosesHL.Transforming growth factor beta-regulated gene expression in a mouse mammary gland epithelial cell line.Breast Cancer Res2003;
5:R187–98
80.
WeijtsBGBakkerWJCornelissenPWLiangKHSchaftenaarFHWestendorpBde WolfCAPaciejewskaMScheeleCLKentLLeoneGSchulte-MerkerSde BruinA.E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1.EMBO J2012;
31:3871–84
81.
DangCVReddyEPShokatKMSoucekL.Drugging the 'undruggable' cancer targets.Nat Rev Cancer2017;
17:502–8
82.
YanCHigginsPJ.Drugging the undruggable: transcription therapy for cancer.Biochim Biophys Acta2013;
1835:76–85
83.
KentLNLeoneG.The broken cycle: E2F dysfunction in cancer.Nat Rev Cancer2019;
19:326–38
84.
KnudsenESWitkiewiczAK.The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies.Trends Cancer2017;
3:39–55
85.
WhittakerSRMallingerAWorkmanPClarkePA.Inhibitors of cyclin-dependent kinases as cancer therapeutics.Pharmacol Ther2017;
173:83–105
86.
NokisalmiPPesonenSEscutenaireSSarkiojaMRakiMCerulloVLaasonenLAlemanyRRojasJCascalloMGuseKRajeckiMKangasniemiLHaavistoEKarioja-KallioAHannukselaPOksanenMKanervaAJoensuuTAhtiainenLHemminkiA.Oncolytic adenovirus ICOVIR-7 in patients with advanced and refractory solid tumors.Clin Cancer Res2010;
16:3035–43
87.
DeanJLThangavelCMcClendonAKReedCAKnudsenES.Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure.Oncogene2010;
29:4018–32
88.
WanXBLongZJYanMXuJXiaLPLiuLZhaoYHuangXFWangXRZhuXFHongMHLiuQ.Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.Carcinogenesis2008;
29:1930–7
89.
SchultzSJFryAMSutterlinCRiedTNiggEA.Cell cycle-dependent expression of Nek2, a novel human protein kinase related to the NIMA mitotic regulator of Aspergillus nidulans. Cell Growth Differ1994;
5:625–35
90.
HamesRSFryAM.Alternative splice variants of the human centrosome kinase Nek2 exhibit distinct patterns of expression in mitosis.Biochem J2002;
361:77–85
91.
WuWBaxterJEWattamSLHaywardDGFardilhaMKnebelAFordEM,
da Cruz e Silva EF, Fry AM. Alternative splicing controls nuclear translocation of the cell cycle-regulated Nek2 kinase. J Biol Chem2007;
282:26431–40
92.
RenBCamHTakahashiYVolkertTTerragniJYoungRADynlachtBD.E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints.Genes Dev2002;
16:245–56
93.
LeeMYMorenoCSSaavedraHI.The E2F activators signal and maintain centrosome amplification in breast cancer cells.Mol Cell Biol2014;
34:2581–99
94.
Harrison PitnerMKSaavedraHI.Cdk4 and nek2 signal binucleation and centrosome amplification in a her2+ breast cancer model.PLoS One2013;
8:e65971
95.
ZengXShaikhFYHarrisonMKAdonAMTrimboliAJCarrollKASharmaNTimmersCChodoshLALeoneGSaavedraHI.The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2. Oncogene2010;
29:5103–12
96.
NabilsiNHRyderDJPeraza-PentonACPoudyalRLooseDSKladdeMP.Local depletion of DNA methylation identifies a repressive p53 regulatory region in the NEK2 promoter.J Biol Chem2013;
288:35940–51
97.
TakahashiYIwayaTSawadaGKurashigeJMatsumuraTUchiRUeoHTakanoYEguchiHSudoTSugimachiKYamamotoHDokiYMoriMMimoriK.Up-regulation of NEK2 by microRNA-128 methylation is associated with poor prognosis in colorectal cancer.Ann Surg Oncol2014;
21:205–12
98.
LaoukiliJKooistraMRBrasAKauwJKerkhovenRMMorrisonACleversHMedemaRH.FoxM1 is required for execution of the mitotic programme and chromosome stability.Nat Cell Biol2005;
7:126–36
99.
WonseyDRFollettieMT.Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe.Cancer Res2005;
65:5181–9
100.
FangYZhangX.Targeting NEK2 as a promising therapeutic approach for cancer treatment.Cell Cycle2016;
15:895–907
101.
FryAMMayorTMeraldiPStierhofYDTanakaKNiggEA.C-Nap1, a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2.J Cell Biol1998;
141:1563–74
102.
BaheSStierhofYDWilkinsonCJLeissFNiggEA.Rootletin forms centriole-associated filaments and functions in centrosome cohesion.J Cell Biol2005;
171:27–33
103.
ManXMegrawTLLimYP.Cep68 can be regulated by Nek2 and SCF complex.Eur J Cell Biol2015;
94:162–72
104.
RapleyJBaxterJEBlotJWattamSLCasenghiMMeraldiPNiggEAFryAM.Coordinate regulation of the mother centriole component nlp by nek2 and plk1 protein kinases.Mol Cell Biol2005;
25:1309–24
105.
LouYYaoJZereshkiADouZAhmedKWangHHuJWangYYaoX.NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling.J Biol Chem2004;
279:20049–57
106.
WeiRNgoBWuGLeeWH.Phosphorylation of the Ndc80 complex protein, HEC1, by Nek2 kinase modulates chromosome alignment and signaling of the spindle assembly checkpoint.Mol Biol Cell2011;
22:3584–94
107.
FuGDingXYuanKAikhionbareFYaoJCaiXJiangKYaoX.Phosphorylation of human Sgo1 by NEK2A is essential for chromosome congression in mitosis.Cell Res2007;
17:608–18
108.
FryAMMeraldiPNiggEA.A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators.EMBO J1998;
17:470–81
109.
GuZZhouWHuangJYangYWendlandtEXuHHeXTricotGZhanF.Nek2 is a novel regulator of B cell development and immunological response.Biomed Res Int2014;
2014:621082
110.
WaiDHSchaeferKLSchrammAKorschingEVan ValenFOzakiTBoeckerWSchweigererLDockhorn-DworniczakBPorembaC.Expression analysis of pediatric solid tumor cell lines using oligonucleotide microarrays.Int J Oncol2002;
20:441–51
111.
KokuryoTSengaTYokoyamaYNaginoMNimuraYHamaguchiM.Nek2 as an effective target for inhibition of tumorigenic growth and peritoneal dissemination of cholangiocarcinoma.Cancer Res2007;
67:9637–42
112.
RajagopalanHLengauerC.Aneuploidy and cancer.Nature2004;
432:338–41
113.
ZhangYWangWWangYHuangXZhangZChenBXieWLiSShenSPengB.NEK2 promotes hepatocellular carcinoma migration and invasion through modulation of the epithelial-mesenchymal transition. Oncol Rep2018;
39:1023–33
114.
ChangYYYenCJChanSHChouYWLeeYPBaoCYHuangCJHuangW.NEK2 promotes hepatoma metastasis and serves as biomarker for high recurrence risk after hepatic resection. Ann Hepatol2018;
17:843–56
115.
DasTKDanaDParolySSPerumalSKSinghSJhunHPendseJCaganRLTaleleTTKumarS.Centrosomal kinase Nek2 cooperates with oncogenic pathways to promote metastasis.Oncogenesis2013;
2:e69
116.
MbomBCSiemersKAOstrowskiMANelsonWJBarthAI.Nek2 phosphorylates and stabilizes beta-catenin at mitotic centrosomes downstream of Plk1.Mol Biol Cell2014;
25:977–91
117.
ZhouWYangYXiaJWangHSalamaMEXiongWXuHShettySChenTZengZShiLZangariMMilesRBearssDTricotGZhanF.NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.Cancer Cell2013;
23:48–62
118.
KaowinnSOhSMoonJYooAYKangHYLeeMRKimJEHwangDYYounSEKohSSChungYH.CGK062, a small chemical molecule, inhibits cancer upregulated gene 2induced oncogenesis through NEK2 and betacatenin.Int J Oncol2019;
54:1295–305
119.
ZhaoDHanWLiuXCuiDChenY.Deguelin inhibits epithelial-to-mesenchymal transition and metastasis of human non-small cell lung cancer cells by regulating NIMA-related kinase 2. Thorac Cancer2017;
8:320–27
120.
KokuryoTHibinoSSuzukiKWatanabeKYokoyamaYNaginoMSengaTHamaguchiM.Nek2 siRNA therapy using a portal venous port-catheter system for liver metastasis in pancreatic cancer.Cancer Sci2016;
107:1315–20
121.
WuGQiuXLZhouLZhuJChamberlinRLauJChenPLLeeWH.Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal.Cancer Res2008;
68:8393–9
122.
LiuXWineyM.The MPS1 family of protein kinases.Annu Rev Biochem2012;
81:561–85
123.
PikeANFiskHA.Centriole assembly and the role of Mps1: defensible or dispensable?Cell Div2011;
6:9
124.
StuckeVMSilljeHHArnaudLNiggEA.Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication.EMBO J2002;
21:1723–32
125.
DeLucaJGGallWECiferriCCiminiDMusacchioASalmonED.Kinetochore microtubule dynamics and attachment stability are regulated by Hec1.Cell2006;
127:969–82
126.
MaciejowskiJGeorgeKATerretMEZhangCShokatKMJallepalliPV.Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signaling.J Cell Biol2010;
190:89–100
127.
FiskHAMattisonCPWineyM.Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression.Proc Natl Acad Sci USA2003;
100:14875–80
128.
MohlDAHuddlestonMJCollingwoodTSAnnanRSDeshaiesRJ.Dbf2-Mob1 drives relocalization of protein phosphatase Cdc14 to the cytoplasm during exit from mitosis.J Cell Biol2009;
184:527–39
129.
MattisonCPStumpffJWordemanLWineyM.Mip1 associates with both the Mps1 kinase and actin, and is required for cell cortex stability and anaphase spindle positioning.Cell Cycle2011;
10:783–93
130.
StraightPDGiddingsTHJr.WineyM.Mps1p regulates meiotic spindle pole body duplication in addition to having novel roles during sporulation. Mol Biol Cell2000;
11:3525–37
SchmandtRHillMAmendolaAMillsGBHoggD.IL-2-induced expression of TTK, a serine, threonine, tyrosine kinase, correlates with cell cycle progression.J Immunol1994;
152:96–105
133.
PalframanWJMeehlJBJaspersenSLWineyMMurrayAW.Anaphase inactivation of the spindle checkpoint.Science2006;
313:680–4
134.
LiuXLiaoWYuanQOuYHuangJ.TTK activates Akt and promotes proliferation and migration of hepatocellular carcinoma cells. Oncotarget2015;
6:34309–20
135.
LeeMYMarinaMKingJLSaavedraHI.Differential expression of centrosome regulators in Her2+ breast cancer cells versus non-tumorigenic MCF10A cells.Cell Div2014;
9:3
136.
KingJLZhangBLiYLiKPNiJJSaavedraHIDongJT.TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer.Oncogenesis2018;
7:69
137.
WangXDaiW.Shugoshin, a guardian for sister chromatid segregation.Exp Cell Res2005;
310:1–9
138.
KitajimaTSKawashimaSAWatanabeY.The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis.Nature2004;
427:510–7
139.
YaoYDaiW.Shugoshins function as a guardian for chromosomal stability in nuclear division.Cell Cycle2012;
11:2631–42
140.
KaramyshevaZDiaz-MartinezLACrowSELiBYuH.Multiple anaphase-promoting complex/cyclosome degrons mediate the degradation of human Sgo1.J Biol Chem2009;
284:1772–80
141.
FuGHuaSWardTDingXYangYGuoZYaoX.D-box is required for the degradation of human Shugoshin and chromosome alignment.Biochem Biophys Res Commun2007;
357:672–8
142.
McGuinnessBEHirotaTKudoNRPetersJMNasmythK.Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells.PLoS Biol2005;
3:e86
143.
WangXYangYDaiW.Differential subcellular localizations of two human Sgo1 isoforms: implications in regulation of sister chromatid cohesion and microtubule dynamics. Cell Cycle2006;
5:635–40
144.
WangXYangYDuanQJiangNHuangYDarzynkiewiczZDaiW.sSgo1, a major splice variant of Sgo1, functions in centriole cohesion where it is regulated by Plk1.Dev Cell2008;
14:331–41
145.
KitajimaTSHaufSOhsugiMYamamotoTWatanabeY.Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization.Curr Biol2005;
15:353–9
146.
TangZSunYHarleySEZouHYuH.Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis.Proc Natl Acad Sci USA2004;
101:18012–7
147.
LeeJKitajimaTSTannoYYoshidaKMoritaTMiyanoTMiyakeMWatanabeY.Unified mode of centromeric protection by shugoshin in mammalian oocytes and somatic cells.Nat Cell Biol2008;
10:42–52
148.
KitajimaTSSakunoTIshiguroKIemuraSNatsumeTKawashimaSAWatanabeY.Shugoshin collaborates with protein phosphatase 2A to protect cohesin.Nature2006;
441:46–52
149.
RaoCVSangheraSZhangYBiddickLReddyALightfootSJanakiramNBMohammedADaiWYamadaHY.Systemic chromosome instability resulted in colonic transcriptomic changes in metabolic, proliferation, and stem cell regulators in Sgo1−/+ mice.Cancer Res2016;
76:630–42
150.
WangLHYenCJLiTNEloweSWangWCWangLH.Sgo1 is a potential therapeutic target for hepatocellular carcinoma.Oncotarget2015;
6:2023–33
151.
YamadaHYZhangYReddyAMohammedALightfootSDaiWRaoCV.Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice.Carcinogenesis2015;
36:429–40
152.
Murakami-TonamiYIkedaHYamagishiRInayoshiMInagakiSKishidaSKomataYJanKTakeuchiIKondoYMaedaTSekidoYMurakamiHKadomatsuK.SGO1 is involved in the DNA damage response in MYCN-amplified neuroblastoma cells.Sci Rep2016;
6:31615
153.
YamadaHYKumarGZhangYRubinELightfootSDaiWRaoCV.Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung.Oncogenesis2016;
5:e256
154.
IwaizumiMShinmuraKMoriHYamadaHSuzukiMKitayamaYIgarashiHNakamuraTSuzukiHWatanabeYHishidaAIkumaMSugimuraH.Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer.Gut2009;
58:249–60
155.
MuJFanLLiuDZhuD.Overexpression of shugoshin1 predicts a poor prognosis for prostate cancer and promotes metastasis by affecting epithelial-mesenchymal transition.Onco Targets Ther2019;
12:1111–18
156.
YamadaHYYaoYWangXZhangYHuangYDaiWRaoCV.Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis.Cell Cycle2012;
11:479–88
157.
Diaz-MartinezLAYuH.Sgo1 as a guardian of chromosome stability.Cell Cycle2012;
11:650–1
158.
ShiZTaylorAWHuGGillTWittertGA.Rice intake, weight change and risk of the metabolic syndrome development among Chinese adults: the Jiangsu Nutrition Study (JIN). Asia Pac J Clin Nutr2012;
21:35–43
159.
WatanabeYKitajimaTS.Shugoshin protects cohesin complexes at centromeres.Philos Trans R Soc Lond B Biol Sci2005;
360:515–21, discussion 21
160.
LeeNRKimHSKimYSKwonMHChoiKSLeeCW.Regulation of the subcellular shuttling of Sgo1 between centromeres and chromosome arms by Aurora B-mediated phosphorylation.Biochem Biophys Res Commun2014;
454:429–35
161.
LiuHRankinSYuH.Phosphorylation-enabled binding of SGO1-PP2A to cohesin protects sororin and centromeric cohesion during mitosis.Nat Cell Biol2013;
15:40–9
162.
PouwelsJKukkonenAMLanWDaumJRGorbskyGJStukenbergTKallioMJ.Shugoshin 1 plays a central role in kinetochore assembly and is required for kinetochore targeting of Plk1.Cell Cycle2007;
6:1579–85
