A number of important cancer-associated covalent modifications of histone genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3′-untranslated regions. We evaluated the effect of single-nucleotide polymorphisms (SNPs) at the miR-502 binding site in the 3′-untranslated region of the SET8 gene on the clinical outcome of non-Hodgkin's lymphomas (NHL).
Methods and Study Design
The miR-502 binding site SNP of rs16917496 in the 3′-untranslated region of SET8 was genotyped with the ligation detection reaction method. The association of rs16917496 with NHL survival was calculated with the log-rank test using the Kaplan-Meier method. Multivariate survival analysis was performed using a Cox proportional hazards model.
Results
Patients carrying the rs16917496 CC genotype had a significantly longer survival time than patients carrying the CT genotype (P = 0.043) or TT genotype (P = 0.086). In addition, rs16917496 was associated independently with the survival of NHL patients in multivariate analysis (CC vs TT, 95% CI: 1.021–3.279, RR: 1.829, P = 0.043; CC vs CT, 95% CI: 1.026–3.339, RR: 1.851, P = 0.041). The association of rs16917496 with NHL survival was further identified in the peripheral T cell lymphoma (pTCL) subtype of NHL at borderline statistically significant levels (P = 0.069).
Conclusion
Our study provides evidence that the SNP in the miRNA binding site of the SET8 3′-untranslated region seems to influence survival of NHL. It may have possible prognostic and survival value in the clinic.
FangJ., FengQ., KetelC.S., WangH., CaoR., XiaL., Erdjument-BromageH., TempstP., SimonJ.A., ZhangY.: Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol, 12: 1086–1099, 2002.
2.
ZhangY., ReinbergD.: Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev, 15: 2343–2360, 2001.
3.
SchottaG., LachnerM., SarmaK., EbertA., SenguptaR., ReuterG., ReinbergD., JenuweinT.: A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev, 18: 1251–1262, 2004.
4.
SandersS.L., PortosoM., MataJ., BählerJ., AllshireR.C., KouzaridesT.: Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell, 119: 603–614, 2004.
5.
JonesP.A., BaylinS.B.: The epigenomics of cancer. Cell, 128: 683–692, 2007.
6.
FragaM.F., BallestarE., Villar-GareaA., Boix-ChornetM., EspadaJ., SchottaG., BonaldiT., HaydonC., RoperoS., PetrieK., IyerN.G., Pérez-RosadoA., CalvoE., LopezJ.A., CanoA., CalasanzM.J., ColomerD., PirisM.A., AhnN., ImhofA., CaldasC., JenuweinT., EstellerM.: Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4is a common hallmark of human cancer. Nat Genet, 37: 391–400, 2005.
7.
YinY., LiuC., TsaiS.N., ZhouB., NgaiS.M., ZhuG.: SET8 recognizes the sequence RHRK20VLRDN within the N terminus of histone H4 and mono-methylates lysine 20. J Biol Chem, 280: 30025–30031, 2005.
8.
CoutureJ.F., CollazoE., BrunzelleJ.S., TrievelR.C.: Structural and functional analysis of SET8, a histone H4Lys-20 methyltransferase. Genes Dev, 19: 1455–1465, 2005.
9.
HuenM.S., SyS.M., van DeursenJ.M., ChenJ.: Direct interaction between SET8 and proliferating cell nuclear antigen couples H4–20 methylation with DNA replication. J Biol Chem, 283: 11073–11077, 2008.
10.
JorgensenS., ElversI., TrelleM.B., MenzelT., EskildsenM., JensenO.N., HelledayT., HelinK., SorensenC.S.: The histone methyltransferase SET8 is required for S-phase progression. J Cell Biol, 179: 1337–1345, 2007.
11.
YinY., YuV.C., ZhuG., ChangD.C.: SET8 plays a role in controlling G1/S transition by blocking lysine acetylation in histone through binding to H4 N-terminal tail. Cell Cycle, 7: 1423–1432, 2008.
12.
HoustonS.I., McManusK.J., AdamsM.M., SimsJ.K., CarpenterP.B., HendzelM.J., RiceJ.C.: Catalytic function of the PR-Set7 histone H4lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability. J Biol Chem, 283: 19478–19488, 2008.
AmbrosV.: The functions of animal microRNAs. Nature, 431: 350–355, 2004.
15.
CalinG.A., CroceC.M.: MicroRNA-cancer connection: the beginning of a new tale. Cancer Res, 66: 7390–7394, 2006.
16.
VenturaA., JacksT.: MicroRNAs and cancer: short RNAs go a long way. Cell, 136: 586–591, 2009.
17.
LandiD., GemignaniF., NaccaratiA., PardiniB., VodickaP., VodickovaL., NovotnyJ., FörstiA., HemminkiK., CanzianF., LandiS.: Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer. Carcinogenesis, 29: 579–584, 2008.
18.
SwerdlowS.H., CampoE., HarrisN.L., JaffeE.S., PileriS.A., SteinH., ThieleJ., VardimanJ.W.: WHO classification of tumours of haematopoietic and lymphoid tissues, p 439. International Agency for Research on Cancer, Lyon, 2008.
19.
SongF., ZhengH., LiuB., WeiS., DaiH., ZhangL., CalinG.A., HaoX., WeiQ., ZhangW., ChenK.: An miR-502–binding site single-nucleotide polymorphism in the 3 -untranslated region of the SET8 gene is associated with early age of breast cancer onset. Clin Cancer Res, 15: 6292–6300, 2009.
20.
GuoZ., WuC., WangX., WangC., ZhangR., ShanB.: A polymorphism at the miR-502 binding site in the 3′-untranslated region of the histone methyltransferase SET8 is associated with hepatocellular carcinoma outcome. Int J Cancer, 131: 1318–1322, 2012.
21.
HanX., KilfoyB., ZhengT., HolfordT.R., ZhuC., ZhuY., ZhangY.: Lymphoma survival patterns by WHO subtype in the United States, 1973–2003. Cancer Causes Control, 19: 841–858, 2008.
22.
WangS.S., MaurerM.J., MortonL.M., HabermannT.M., DavisS., CozenW., LynchC.F., SeversonR.K., RothmanN., ChanockS.J., HartgeP., CerhanJ.R.: Polymorphisms in DNA repair and one-carbon metabolism genes and overall survival in diffuse large B-cell lymphoma and follicular lymphoma. Leukemia, 23: 596–602, 2009.
23.
WangS.S., PurdueM.P., CerhanJ.R., ZhengT., MenasheI., ArmstrongB.K., LanQ., HartgeP., KrickerA., ZhangY., MortonL.M., VajdicC.M., HolfordT.R., SeversonR.K., GrulichA., LeadererB.P., DavisS., CozenW., YeagerM., ChanockS.J., ChatterjeeN., RothmanN.: Common gene variants in the tumor necrosis factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk. PLoS One, 4: e5360, 2009.
24.
DiaoL.P., MaH., WeiG.C., LiT., LiuH.S., LiuL.H., WuL.L., ZhaoG.M., GaoY.H.: Matrix metalloproteinase-2 promoter and tissue inhibitor of metalloproteinase-2 gene polymorphisms in non-Hodgkin's lymphoma. Int J Cancer, 131: 1095–1103, 2012.
25.
DingC., LiR., PengJ., LiS., GuoZ.: A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer. Exp Ther Med, 3: 689–692, 2012.
26.
ShiX., KachirskaiaI., YamaguchiH., WestL.E., WenH., WangE.W., DuttaS., AppellaE., GozaniO.: Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol Cell27: 636–646, 2007.
27.
FabbriM., GarzonR., CimminoA., LiuZ., ZanesiN., CallegariE., LiuS., AlderH., CostineanS., Fernandez-CymeringC., VoliniaS., GulerG., MorrisonC.D., ChanK.K., MarcucciG., CalinG.A., HuebnerK., CroceC.M.: MicroRNA 29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA, 104: 15805–15810, 2007.
28.
TuddenhamL., WheelerG., Ntounia-FousaraS., WatersJ., HajihosseiniM.K., ClarkI., DalmayT.: The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett, 580: 4214–4217, 2006.
29.
BrendleA., LeiH., BrandtA., JohanssonR., EnquistK., HenrikssonR., HemminkiK., LennerP., FörstiA.: Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker. Carcinogenesis, 29: 1394–1399, 2008.
30.
GaoY., HeY., DingJ., WuK., HuB., LiuY., WuY., GuoB., ShenY., LandiD., LandiS., ZhouY., LiuH.: An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1a 3'untranslated region confers risk for hepatocellular carcinoma. Carcinogenesis, 30: 2064–2069, 2009.
31.
YuZ., LiZ., JolicoeurN., ZhangL., FortinY., WangE., WuM., ShenS.H.: Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res, 35: 4535–4541, 2007.
32.
DiaoL.P., YuX.M., GaoY.H., LiY., LiuH.S., LiuL.H., ZhouR.M., WangN., WuL.L., WangS.J.: Association of VEGF genetic polymorphisms with the clinical characteristics of non-Hodgkin's lymphoma. J Cancer Res Clin Oncol, 135: 1473–1481, 2009.
