Literature DB >> 28229117

DNA methylation data for identification of epigenetic targets of resveratrol in triple negative breast cancer cells.

Rubiceli Medina-Aguilar1, Carlos Pérez-Plasencia2, Patricio Gariglio1, Laurence A Marchat3, Ali Flores-Pérez4, César López-Camarillo4, Jaime García Mena1.   

Abstract

Previous studies revealed that some bioactive food components have anti-cancer effects. However epigenetic effects of dietary compound resveratrol are largely unknown in breast cancer cells (M.A. Dawson, T. Kouzarides, 2012) [1]. Here we provide novel data and comparisons of DNA methylation status of promoter gene regions in response to resveratrol treatment at 24 h and 48 h versus untreated MDA-MB-231 breast cancer cells. DNA methylation changes were measured using Array-PRIMES method (aPRIMES) followed by whole-genome hybridization using human DNA methylation promoter microarray NimbleGen HG18 Refseq Promoter 3×720 K array. Our data were associated to corresponding changes in mRNA expression in a set of cancer-related genes. Using gene ontology analysis we also identify cancer-related cellular processes and pathways that can be epigenetically reprogramed by resveratrol. Data in this article are associated to the research articles "Methylation Landscape of Human Breast Cancer Cells in Response to Dietary Compound Resveratrol". Medina Aguilar et al., PLoS ONE 11(6): e0157866. doi:10.1371/journal.pone.0157866 2016 (A.R. Medina, P.C. Pérez, L.A. Marchat, P. Gariglio, M.J. García, C.S. Rodríguez, G.E. Ruíz, et al., 2016) [2]; and "Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells" in Oncology Reports. Medina Aguilar et al., 2016 Jun; 35(6):3696-704. doi: 10.3892/or.2016.4728 (A.R. Medina, P. Gariglio, M.J. García, O.E. Arechaga, S.N. Villegas, C.M. Martínez et al., 2016) [3].

Entities:  

Keywords:  Breast cancer; DNA methylation; Genome-wide methylome; Oncogenes; Resveratrol; Tumor suppressor genes

Year:  2017        PMID： 28229117      PMCID： PMC5312642          DOI： 10.1016/j.dib.2017.02.006

Source DB:  PubMed          Journal:  Data Brief        ISSN： 2352-3409


Specifications Table Value of the data First analysis on DNA methylation of promoter genes in triple negative breast cancer cells treated with resveratrol, spanning 27,728 CpG loci. Provides genomic data indicating that resveratrol impacts the epigenetic landscape by changing DNA methylation status of specific oncogenes and tumor suppressor genes in breast cancer cells. Analyses indicate that resveratrol epigenetically alters regulation of particular genes involved in cancer in triple negative breast cancer cells. Data provided here serves as a novel and free resource for researchers working in the field of epigenetic regulation of cancer related genes in response to naturally occurring dietary compounds.

Data

In this study we performed a genome-wide survey of DNA methylation in MDA-MB-231 triple-negative breast cancer cells exposed to resveratrol [1], [3]. To determine the methylated and unmethylated DNA regions in the promoters of genes we used Array-PRIMES method (aPRIMES) [[4], Fig. 1]. The extensive annotation of peaks differentially enriched for DNA methylation and peak comparisons between the MDA-MB-231 breast cancer cells treated with resveratrol at 24 h and 48 h versus untreated cells (Table 1, Table 2) were performed using the DEVA 1.2.1 software [2]. At 24 h treatment, 338 out of 2035 hypermethylated genes correspond to cancer genes; and 92 out of 1738 hypomethylated genes correspond to cancer genes. At 48 h treatment, 137 out of 1869 hypermethylated genes were cancer genes; and 288 out of 1661 hypomethylated genes are cancer genes (Table 3, Table 4). In addition, differentially methylated probes and differentially expressed genes were identified between the MDA-MB-231 cells treated with resveratrol at 24 h and 48 h and the MDA-MB-231 untreated. The integrative analysis of DNA methylation and gene expression at different times of resveratrol exposure showed that changes in DNA methylation were associated to corresponding changes in mRNA expression in a set of cancer-related genes (Table 5, Table 6).
Fig. 1

Array-PRIMES procedure and NimbleGen HG18 Refseq Promoter 3×720 K arrays analysis. Genomic DNA (500 ng) was restricted to completion with MseI restriction enzyme. Then, DNA fragments produced by MseI were subjected to linker-mediated PCR. Half of the resulting ligated MseI fragments were digested with McrBC restriction enzyme while the other half of MseI fragments was digested with the two methylation-sensitive endonucleases HpaII and BstUI. The experimental and control DNA was labeled with Cy3 and Cy5 nonamers. Methylated DNA fractions are highlighted in red and are expected to result in positive ratios and green spots indicate unmethylation and are to have negative ratios. DNA methylation analysis raw data was normalized and differential intensity of each probe compared with input control was calculated using the NimbleGen software DEVA. Average fold change (experimental IP sample versus Control input sample) in a range of 2.44 kb upstream and 610 bp downstream window from RefSeq transcription start sites (TSS). Modified from Pfister, S., Schlaeger, C., Mendrzyk, F., Wittmann, A., Benner, A., Kulozik, A., et al. Array-based profiling of reference-independent methylation status (aPRIMES) identifies frequent promoter methylation and consecutive downregulation of ZIC2 in pediatric medulloblastoma. Nucleic Acids Res. (2007) 35:e51.

Table 1

Annotation of peak values indicating differentially enriched DNA methylation between the MDA-MB-231 breast cancer cells treated with resveratrol at 24 h versus non-treated cells.

ChromosomeData startData endPeak value (≥2)Gene nameAccession number
chr8178482917862082,64ARHGEF10NM_052838
chrX152195215227852,63ASMTLNM_004574
chr1760265001602661582,55PLEKHM1PNM_001098813
chr111256418361256428882,54SRPRNM_001113491
chr12284817932284825382,53GALNT2NM_001154458
chr1598649690986503442,50ADAMTS17NM_130786
chr1874927964749290292,50ATP9BNM_033110
chr11294109729425492,50NAP1L4NM_001080438
chr4270331027039442,49FAM193ANR_024035
chr1713340300133409552,49HS3ST3A1NM_001086
chr8641161264123592,48MCPH1NM_014911
chr2218274404182754772,48TXNRD2NM_001088
chr5153658715372402,48LPCAT1NM_000350
chr71547180391547195082,46INSIG1NM_012089
chr101207916011207922502,45EIF3ANM_203444
chr1777869583778712122,44CD7NM_033151
chr91151019381151035492,44RNF183NM_000392
chr141049826061049832412,44MTA1NM_001023587
chr51407475191407482472,42PCDHGB4NM_001171
chr101058359611058370222,42COL17A1NR_003569
chr81456422111456430502,41NFKBIL2NR_023387
chr4179815217988032,41LETM1NM_007011
chr1910113471101141312,41DNMT1NM_020676
chr21216996711217003162,41TFCP2L1NM_007313
chr121190188251190195662,41RAB35NM_001003408
chr7184748718481122,40MAD1L1NM_020469
chr1090702575907034402,40ACTA2NM_001092
chr1952680045526810972,40KPTNNM_032169
chr2060208995602096422,40GTPBP5NM_000017
chr91296925271296931882,39ST6GALNAC6NM_001609
chr1098730453987315982,39C10orf12NM_022735
chr2217010564170118972,39USP18NM_001039844
chr71282024921282032412,38OPN1SWNM_020321
chr17226488222655222,38LOC284009NM_022914
chr1761726971617280242,38PRKCANM_000789
chr823622819236236632,37NKX2-6NM_015831
chr543075569430767242,37C5orf39NM_147161
chr11998820461998829012,37NAV1NM_018473
chr993900029939006622,37SPTLC1NM_006821
chr124599933246006932,37C1orf201NM_007274
chr2146892750468934892,37PRMT2NM_005469
chr31850267061850285732,36MAP6D1NM_001037171
chr286104655861055022,36LOC90784NM_004035
chr6308534430859952,35BPHLNM_003501
chr265394212653948392,35SPRED2NM_001142807
chr12274714862274728102,34RAB4ANM_001111036
chr2060293922602945832,34OSBPL2NM_152282
chr227044598270452422,33MAPRE3NM_033068
chr348454873484557072,33CCDC51NM_052957
chr10113778111384922,33WDR37NM_025149
chr2056158151561598072,33C20orf85NR_023316
chr53548623574572,32AHRRNM_032501
chr91352670131352680482,32REXO4NM_001141945
chr121036747471036753982,32CHST11NM_001101
chr438366523383672502,32KLF3NM_005159
chr2218131439181320802,32TBX1NM_001615
chr12159404215947142,31WNT5BNM_016188
chr516754086167548212,30MYO10NM_006686
chr11543722131543728662,30LMNANM_001102
chr21518275491518281902,29RBM43NM_024855
chr1492722258927228912,29C14orf109NM_001616
chr71584052471584059102,29WDR60NM_001107
chr827907931279084732,29SCARA5NM_003474
chr121318185641318204432,28ANKLE2NM_023038
chr675968244759688932,28COL12A1NM_021794
chr71435870441435878022,27OR2A7NM_139026
chr91248354461248373242,27GPR21NM_139055
chr2043163505431640522,26KCNS1NM_139056
chr1740925157409263192,26PLEKHM1NM_139057
chr71435788731435795442,26OR2A20PNM_021599
chr534020027340219362,26SLC45A2NM_014694
chr131129177721129184072,26CUL4ANM_006869
chr596234968962360982,25ERAP2NM_001025107
chr990794507907956552,25C9orf47NM_001145407
chr1420225056202265872,25ANGNM_018702
chr1916294245162949912,25KLF2NM_052853
chr2145063979450645042,24SUMO3NM_021116
chr1666500283665010202,24PSKH1NM_001116
chr1612118128121188352,24SNX29NM_014190
chr12001224392001234742,24SHISA4NM_144650
chr91389040051389046722,24TRAF2NM_018269
chr271544899715460502,24DYSFNM_001127687
chr11638175791638183162,23LOC400794NM_024866
chr744089644440903012,23POLMNM_001081976
chr11445395101445409552,23GPR89ANM_199162
chr6508014550808482,23LYRM4NM_000679
chr1232338623240292,23RER1NM_000684
chrX1342570811342577082,23ZNF75DNM_001619
chr71371829641371846382,22DGKINM_007002
chr2061372176613738252,22ARFGAP1NM_001114176
chr350351011503527392,22RASSF1NM_001134647
chr101349731761349742522,22ZNF511NR_026892
chr31893779101893790892,22FLJ42393NM_152406
chr91391174691391180982,22MAN1B1NM_014423
chr1012913471129151722,22LOC283070NR_003228
chr2221740231217416022,22RTDR1NM_014914
chr1670115140701162822,22CHST4NM_001135189
chr61320636241320643822,22OR2A4NM_018238
chr1738247695382493482,21PSME3NM_001012727
chr51792092131792098622,21C5orf45NM_020132
chr22189274062189285192,20C2orf62NM_020133
chr78288458295822,20SUN1NM_198576
chr115955401159566742,20FBLIM1NM_001138
chr1955122520551232592,20NUP62NM_000687
chr51407423591407432982,19PCDHGA7NM_006621
chr11593557301593567842,19NIT1NM_020731
chr1742639212426403912,19MYL4NM_001624
chr1949727224497278532,19CEACAM20NM_006303
chr7472409647248452,19FOXK1NM_001042478
chr17365287636536592,19ITGAENM_016282
chr11458648891458660552,19GPR89BNM_003488
chr1075200738752015872,19SEC24CNM_007200
chr1071601773716024362,19SAR1ANM_001136562
chr71119075721119082042,19C7orf53NM_004857
chr1046501205465022482,19PPYR1NM_014371
chr11549660201549667482,18C1orf66NM_001145289
chr51768701761768710492,18DDX41NM_005163
chr12157491815755762,18FBXL14NM_001098632
chr1164609997646106432,18ZFPL1NM_181690
chr299284710992855652,17LYG1NM_001012398
chr2061040935610419232,17C20orf11NM_000031
chr1842165845421674182,17RNF165NM_001017423
chr131619982316206492,17FABP3NM_000693
chr81416280991416287792,17EIF2C2NM_000692
chr5168795916893102,17LOC728613NM_000691
chr296268657962698912,17LOC285033NM_001182
chr101288634881288641272,17FAM196ANM_000034
chr439158359391589282,17LOC401127NM_024105
chr91352108011352119722,16SURF1NM_139178
chr31134951551134958272,16SLC9A10NM_017758
chr1734137596341385452,16MLLT6NM_000697
chr572449727724507722,16TMEM171NM_001139
chr51407806981407814772,16PCDHGA11NR_002710
chr2239514927395153742,15SLC25A17NM_001140
chr12251921452251928702,15CABC1NM_000698
chr1165440964654423372,15C11orf68NM_001102406
chr71517902001517907532,15LOC100128822NM_020778
chr2132594464325951192,15MRAPNM_139163
chr41873019731873025982,15FAM149ANM_006492
chr1420930859209325242,14CHD8NM_021926
chr21526649221526657002,14CACNB4NM_001633
chr17793330879341432,14ALOX12BNM_001144
chr12191210142191216722,14HLXNM_030943
chr227457537274591702,14PPM1GNM_000036
chr1715463136154637092,14CDRT1NM_000480
chr373017682730184392,13GXYLT2NM_133463
chr2219383009193843892,13TMEM191ANM_001033569
chr1952711228527119382,13NAPANR_026903
chr131131573001131581532,13DCUN1D2NM_001002244
chr116832002168324492,13CROCCP2NM_013366
chr101056065121056074502,13SH3PXD2ANM_001145
chr7627940862801472,13CYTH3NM_015305
chr121233746871233759422,13NCOR2NM_001146
chr167269497275982,13NARFLNM_001118887
chr141047841281047850572,12BRF1NM_001142446
chr2145185933451866742,12C21orf70NM_020987
chr999001128990016842,12ZNF322BNM_016376
chr1162403221624040932,12SLC3A2NM_054027
chr131128511481128516812,12F10NM_015114
chr20464831646491832,12PRNDNM_016552
chr164637344650612,12RAB11FIP3NM_017664
chr2048178979481802502,12TMEM189NM_013275
chr143658960436608152,12KIAA0467NM_152345
chr190231647902324822,12GEMIN8P4NR_026868
chr1933850793391582,11SPSB1NM_001012421
chr12019629162019636472,11ATP2B4NM_001012419
chr1561674213616747822,11FBXL22NM_001098805
chr91352142871352150302,11SURF2NM_144994
chr111166061981166068462,11PCSK7NM_133475
chr723421191234219182,11IGF2BP3NR_026556
chr51801893491801902182,11LOC729678NR_027020
chr51407729111407735682,11PCDHGA10NM_153697
chr1946593106465938612,10EXOSC5NM_001115116
chr1532183123321837502,10PGBD4NM_138797
chr71341125941341133252,10CALD1NM_024669
chr1584102740841033872,10KLHL25NM_023016
chr19237964023818042,10LMNB2NM_001105576
chr4850461085074742,10C4orf23NM_020140
chr2131952040319526962,10SOD1NM_018043
chr71003221371003227742,10SRRTNM_006305
chr414984971149858562,10C1QTNF7NM_012403
chr227657775276586082,09C2orf16NM_012404
chr1242994324304682,09PANK4NR_003601
chr1354659335472462,09WDR8NM_174890
chr111187089741187095082,09RNF26NM_005139
chr1686505816865064702,09CA5ANM_001153
chr4137434913750942,09CRIPAKNM_001040084
chr1420525685205275402,09METT11D1NM_001630
chr31993636931993642362,09FAM157ANM_001637
chr101336471361336478782,09BNIP3NM_001158
chr882769155827697292,09SLC10A5NR_001557
chr1332487045324877002,08KLNM_001128426
chr1916001870160026332,08FLJ25328NM_012305
chr31600008661600019252,08MFSD1NM_001025205
chr555068613550698362,08DDX4NM_001077523
chr131132130131132136462,08TMCO3NM_006051
chr842413598424142652,08SLC20A2NM_005883
chr2249319516493200892,08ODF3BNM_153360
chr91246827401246832872,08RC3H2NM_001640
chr1174136170741372222,08RNF169NM_080649
chr91289257551289268512,07RALGPS1NM_001145646
chr31505334991505340682,07TM4SF18NM_015957
chr1210972275109737432,07PRR4NM_198544
chr22198160082198167642,07GLB1LNM_017413
chr599751772997524072,07LOC100133050NM_144772
chr61615024141615037682,07NCRNA00241NM_000482
chr1775803209758038472,07SGSHNM_006789
chr1736558970365598262,07KRTAP4-5NM_014508
chr2132671648326732912,07URB1NM_145298
chr204730974740512,06CSNK2A1NM_021822
chr111282819121282824652,06KCNJ5NM_000483
chr1756835395568361422,06TBX2NM_001647
chr1718371849183728652,06FAM106ANM_001638
chr1163707734637081892,06STIP1NM_001136541
chr811386701113877882,06BLKNM_030643
chr19752760175283512,06PNPLA6NM_001130415
chr269602478696031372,06AAK1NM_019101
chr2144030904440317432,06RRP1NM_001136131
chr71345488611345492992,06WDR91NM_018171
chr61092739951092748342,06ARMC2NM_175069
chr115796225802852,06PHRF1NM_001170
chr61583204721583221402,06SYNJ2NR_026558
chr61604320811604342422,06LOC729603NM_001169
chrX1533742081533746402,06SLC10A3NM_173800
chr1813252330132532832,05C18orf1NM_001135190
chr1267014287670148492,05MDM1NM_022481
chr2236858553368592242,05PLA2G6NM_018209
chr21057263921057276232,05NCK2NM_006421
chr1686005066860057332,05ZCCHC14NM_012402
chr772355435723560842,05NSUN5NM_003224
chr1193939850939407102,05PIWIL4NM_000045
chr71435602501435608052,05OR2A1NM_021226
chr799534641995352942,04MCM7NM_020876
chr1095712773957136112,04PIPSLNM_001007231
chr2045300989453016622,04ZMYND8NM_199282
chr999500965995016162,04XPANM_020754
chr91236985421236991932,04TTLL11NM_025251
chr51537617911537636482,04GALNT10NM_181335
chr101119549221119560612,04MXI1NM_014629
chr935803160358040072,04HINT2NM_018125
chr164441661644424092,04UBE2UNM_173728
chr2043949136439505762,04C20orf165NM_015320
chrX48714505487151342,04GRIPAP1NM_145735
chr2218092827180950502,04GP1BBNM_006015
chr11096255941096263412,04PSRC1NM_001040025
chr168072396680730702,04GNG12NM_001037164
chr121121086231121093962,04C12orf52NM_001037174
chr81449844741449853272,03PUF60NM_015161
chr1945247606452488392,03ZNF780BNM_016638
chr937775709377763722,03EXOSC3NM_032131
chr1323049798230504682,03TNFRSF19NM_025139
chr2145511110455117632,03POFUT2NM_016608
chr51407523691407531162,03PCDHGA8NM_014862
chr1248964014489646682,03LIMA1NM_001178
chr111165735321165741832,03SIDT2NM_152862
chr91265753111265758382,03NR6A1NM_032487
chr618494407184948352,03RNF144BNM_001080523
chr2219717794197185682,03SLC7A4NM_001085427
chr21909795851909802382,03MFSD6NM_000047
chr823484771234854962,03SLC25A37NM_001012301
chr6155062915525742,03FOXC1NM_021071
chr81460214401460218892,03ZNF7NM_139058
chr772064829720652862,03NSUN5P2NM_018482
chr91295822031295830462,02SH2D3CNM_001135191
chr1074926545749273172,02USP54NM_001040445
chr12263617652263624902,02MRPL55NM_024701
chr798470784984715332,02SMURF1NM_212556
chr71006757311006762782,02FIS1NM_016150
chr31297092771297100162,02LOC90246NM_016116
chr1869967812699685702,02C18orf55NM_177999
chr19275040327511322,02THOP1NM_014034
chr4780440178055502,02AFAP1ASNM_004674
chr2051926997519275662,02SUMO1P1NM_001672
chr31977779801977789102,02WDR53NM_004043
chr1166245244662462912,02SPTBN2NM_004192
chr19208223720829922,02AP3D1NM_152792
chr1171492967714942312,02LRTOMTNM_024083
chr51146283331146288852,01PGGT1BNM_014065
chr690081076900817252,01GABRR2NM_198186
chr71497319811497324282,01LOC728743NM_018188
chr2237738715377393182,01APOBEC3CNM_031921
chr2037022165370229002,01DHX35NM_001039211
chr1157262894572635322,01TMX2NM_033064
chr131131438501131445002,01ADPRHL1NM_001030287
chr17455482945557912,01PELP1NM_030803
chr81039467481039472892,01AZIN1NM_033388
chr270635358706361072,01TGFANM_024085
chr1916145082161457382,01CIB3NM_024490
chr91157026491157033482,01ZNF618NM_032189
chr633278127332789832,01SLC39A7NM_024524
chr644228307442288322,01TMEM63BNM_000702
chr1035574617355752792,01CCNYNM_001135765
chr111302925971302934522,01SNX19NM_174953
chr1736507252365080012,01KRTAP4-8NM_001001396
chr51111236141111242762,01C5orf13NM_001002031
chr111240506831240512362,00SPA17NM_001003713
chr4697597669766252,00TBC1D14NM_001017971
chr1419994926199954872,00APEX1NM_005765
chr268813855688143862,00ARHGAP25NM_012463
chr101060840591060847152,00ITPRIPNM_152565
chr159532773595336692,00FGGYNM_145230
chr101267017871267024222,00CTBP2NM_001695
chr71496559541496573922,00LRRC61NM_144583
chr1959300295937292,00TMEM201NM_080653
chr1775364548753655072,00CBX2NM_138282
chr140191655401924022,00MFSD2ANM_015941
chr439721670397223412,00LOC344967NM_001105529
chr125106856251074032,00RUNX3NM_138813
Table 2

Annotation of peak values indicating differentially enriched DNA methylation between the MDA-MB-231 breast cancer cells treated with resveratrol at 48 h versus non-treated cells.

ChromosomeData startData endPeak value (≥ 2)Gene nameAccession number
chr2051631293516319422,33ZNF217NM_006526
chr71297181401297192632,33CPA4NM_016352
chr141043110191043116662,32AKT1NM_005163
chr11485117611485124202,31C1orf54NM_024579
chr1423710633237113732,31REC8NM_005132
chr21518275491518281902,30RBM43NM_198557
chr71585098141585104852,27LOC154822NR_024394
chr1723822375238234052,26SLC13A2NM_001145976
chr1495011537950125802,24C14orf49NM_152592
chr1422458926224602892,24PRMT5NM_006109
chr1099197678991982112,24ZDHHC16NM_198046
chr22384308092384316462,20RAMP1NM_005855
chr143198303431994962,20SLC2A1NM_006516
chr61439315741439322382,19LOC285740NR_027113
chr81310229981310234362,17FAM49BNM_016623
chr822024534220252872,17NUDT18NM_024815
chr1163747908637490572,16TRPT1NM_031472
chr4349622034968692,16LRPAP1NM_002337
chr734840781348414382,15NPSR1NM_207173
chr594752293947530442,15FAM81BNM_152548
chr11998821341998829912,14NAV1NM_020443
chr12078655422078662802,14LAMB3NM_001017402
chr1616231473162321982,14NOMO3NM_001004067
chr166230912662315962,13PDE4BNM_001037341
chr886478784864795212,13CA1NM_001128829
chr211210550112112212,13PQLC3NM_152391
chr111843395118439832,12NPPBNM_002521
chr2036486806364875352,12SNORA71BNR_002910
chr339125418391265672,12TTC21ANM_145755
chrX99080841990818732,12LOC442459NR_024608
chr2051926997519275662,11SUMO1P1NR_002189
chr61677188031677203482,11TCP10NM_004610
chr775207943752086302,10HIP1NM_005338
chr31134951551134957282,10SLC9A10NM_183061
chr17881109288117492,10PIK3R5NM_001142633
chrX69199270692000372,10OTUD6ANM_207320
chr1490790629907924322,09GPR68NM_003485
chr1914042256140431172,09LOC113230NR_024282
chr11778256071778265562,09TDRD5NM_173533
chr1173337521733383482,08DNAJB13NM_153614
chr1377212180772133372,08SLAIN1NM_001040153
chr274607544746091042,07AUP1NM_181575
chr1630301072303017232,06Septin 1NM_052838
chr6308534430859952,06BPHLNR_026650
chr2036506395365069252,06SNHG11NR_003239
chr1953768383537689552,06SULT2B1NM_177973
chr20394511739455702,05RNF24NM_001134338
chr11991293161991300712,05C1orf106NM_018265
chr1736276397362770402,05KRT12NM_000223
chr5650074365015882,04UBE2QL1NM_001145161
chr274533281745338542,02INO80BNM_031288
chr71000929511000939942,02ACTL6BNM_016188
chr11098357411098365942,02ATXN7L2NM_153340
chr101274557571274568002,02MMP21NM_147191
chr1119327809193289802,02NAV2NM_001111018
chr1162147480621478672,02B3GAT3NM_012200
chr21278924551278931182,02PROCNM_000312
chr2017622453176228992,01BANF2NM_001159495
chr1169934732699354652,01CTTNNM_005231
chr1570278412702793712,01PKM2NM_182470
chr1248782280487832452,01GPD1NM_005276
chr11507532731507540182,01CRCT1NM_019060
chr154786266547871212,01ACOT11NM_147161
chr1419994926199954872,00APEX1NM_080649
chr136320120363216202,00TEKT2NM_014466
Table 3

List of hypermethylated and hypomethylated cancer genes in MDA-MB-231 cells expose to resveratrol at 24 h.

Out of 2035 Hypermethylated genes, 338 were cancer-related genes:ABCC5, ABL1, ACD, ACE, ACTB, ACTL7B, ACVR2A, ADCY1, AFF4, AJAP1, AKAP13, AKT1, ALOX12, ANGPT1, ANK3, ANKLE2, ANKRD24, APOBEC2, ARID1A, ARNT2, ASPSCR1, ATP10A, ATP2A2, ATXN3L, AXIN1, BCL2L10, BCL7A, BCOR, BMPR1A, BRD3, BTG2, C10ORF119 (MCMBP), C10ORF2, C21ORF29 (TSPEAR), C3, CACNA1D, CACNA1H, CAMTA1, CARD11, CARS, CBFA2T3, CBLB, CCDC41 (CEP83), CCDC6, CCDC81, CCNL1, CCR5, CDC25C, CDC42BPB, CDC73, CDHR2, CDHR3, CDK6, CDKN1A, CDYL, CHD3, CHD4, CIC, CNTNAP1, COL1A1, COL4A2, COL5A1, CREB3L1, CREBBP, CRLF2, CRTC1, CSDE1, CSH1, CSNK2B, CTCF, CYFIP1, CYLD, CYTSB (SPECC1), DCAF4L2, DCHS1, DCTN1, DDX41, DICER1, DIP2C, DLC1, DLEU2, DLG3, DNMT1, DNMT3A, DOCK8, DOT1L, DPP6, DRD5, DST, DYNC1I1, EGFR, EIF1AX, EIF3A, ELN, EPB41L3, EPHA1, EPHB4, ESPL1, EXOC2, EYA4, EYS, EZH2, F8, FAM123B (AMER1), FAM171A1, FAM22A (NUTM2A), FAM46C, FAT4, FBXO32, FGF19, FGFR2, FGFR3, FGFR4, FLCN, FMN2, FOXO1, FRMD7, FYN, FZD3, GATA2, GLI3, GLIPR2, GLTSCR1, GML, GNA11, GPR123, GRB2, HDAC9, HERC2, HIP1, HIST1H2AL, HIST1H3D, HLF, HOXA7, HOXD13, HPD, HSP90AA1, IDH2, IL1B, IRF2, ITGA4, JAK2, KBTBD11, KCNJ5, KDM2A, KDM2B, KDM5C, KDSR, KIAA0427 (CTIF), KIAA1024, KIAA1549, KIAA1751 (CFAP74), KIAA1804, KIF1B, KIF5B, KLF2, KLF6, KLHDC4, KLHL6, KNDC1, LDB1, LETM1, LRP2, LTK, MACF1, MAFA, MAP2K2, MAP3K1, MED1, MEN1, MLL (KMT2A), MLL3 (KMT2C), MLLT1, MLLT4, MLLT6, MMP13, MN1, MNX1, MPL, MRPS31, MSH2, MSN, MTOR, MTUS2, MYH11, MYO18B, MYO1B, MYO1G, MYO9A, MYST3 (KAT6A), NCOR2, NEURL4, NF2, NFE2L3, NIN, NLRP3, NOTCH1, NOTCH2, NOTCH3, NR4A3, NSD1, NTRK1, NUAK1, NUDT14, NUP98, ODZ2 (TENM2), OLIG2, OR2A42, OTOP1, PABPC1, PAG1, PAIP1, PAX5, PAX8, PBX1, PCSK6, PCSK7, PDCD6, PDE4DIP, PDGFB, PDGFRA, PDGFRB, PDZD2, PFKP, PHC2, PI4KA, PIK3AP1, PIK3C2B, PIK3CD, PIK3CG, PIK3R1, PKD1L2, PKP4, PLB1, PLCG1, PLXNA2, PLXNA3, PLXND1, PMS2, PNKD, PNN, POU5F1, PPARG, PPM1D, PRDM16, PRIC285 (HELZ2), PRKACA, PRKAR1A, PRKX, PTPN14, PTPRB, PTPRD, PXDN, RABEP1, RADIL, RALGDS, RBMX, RECQL4, RET, RGS12, RHOB, RHOH, RIPK1, RNF213, RNF43, RPS27, RPTOR, RUFY1, RUNDC2A (SNX29), RUNX1, RXRA, RYR2, SCN11A, SCN5A, SDHAF2, SDHB, SEPT7P2, SGK1, SH2B3, SH3GL1, SLC12A6, SLC9A3R1, SMARCA4, SMARCE1, SMC3, SORCS2, SOX2, SRCAP, SRSF3, SS18L1, ST6GAL2, STAT3, STC1, STK19, STYK1, SYNE2, TAF1, TAL1, TAL2, TBX18, TCHH, TERT, TFDP1, TFPT, TLL2, TLX3, TMEM132D, TMSL3 (TMSB4XP8), TNFAIP3, TNFRSF17, TNFSF8, TOP1, TP53, TPM4, TRAF7, TRAK1, TRRAP, TTC18 (CFAP70), TUBA3C, U2AF1, UBR5, VWF, WAC, WAS, WDFY3, WHSC1, WIPF2, WNT2, WT1, XBP1, XPA, XPC, ZFR2, ZFX, ZNF331, ZNF469, ZNF497, ZNF750.
Out of 1738 Hypomethylated genes, 92 were cancer-related genes:ABCA7, ABLIM2, AHNAK, ALS2CL, ARHGAP28, ATP2B3, ATP2C2, ATRX, C19ORF26, C1QL2, C2CD4C, CCDC63, CCND1, CCT8L2, CD79B, CDK13, CHD7, CHST1, CLK3, CNGA4, COL9A2, COX6C, CRTC3, CSMD3, CTNNA2, CYP2E1, DCAF12L2, DDB2, EGFLAM, ERCC2, ERCC6, ETV5, EVPL, FAM58A, FLI1, FLT1, FOXO3, FTCD, GNAT1, HCN1, HOXA9, IGF2, IGF2R, IKZF1, IRF4, KEAP1, KHSRP, LIFR, LMX1A, LPHN1, MED12, MSR1, MST1, MST1R, MUC6, MYCL1 (MYCL), MYD88, MYH9, MYOM2, NEUROG2, NRG2, OR51I2, P2RY8, PCDHB6, PHOX2B, PLCH2, POLE, PPP1R3A, PPP6R2, PROM1, RASGEF1A, RFTN1, RPL5, RYR1, SALL3, SEMA5B, SETBP1, SIGLEC1, SOX9, SPTBN4, STK11, TCF3, TLR2, TMPRSS2, TNFRSF14, TRAF5, TSC2, WDR24, WIF1, ZMYND10, ZNF536, ZZEF1.
Table 4

List of hypermethylated and hypomethylated genes in MDA-MB-231 cells expose to resveratrol at 48 h.

Out of 1869 Hypermethylated genes, 137 were cancer-related genes:ABCC5, ACSL6, AFF4, AKAP8, AKT1, ARHGAP32, ARID1B, ATP4A, BCL10, BCL11B, BPTF, BUB1B, C14ORF49 (SYNE3), CACNA1D, CALCR, CANT1, CARD10, CCDC41 (CEP83), CCNB1IP1, CDHR2, CLP1, COL1A1, CSF3R, CSH1, CSMD1, CXCR7 (ACKR3), DLG3, DNMT3A, DOCK2, DOCK8, DSE, EDNRB, EGR2, EIF1AX, EPHA1, ERG, EZH2, FAM171A1, FAM92B, FANCA, FGFR1, FMN2, G6PC, GLI3, GNA11, GNA13, GRB2, GRM8, HEATR7B2 (MROH2B), HERPUD1, HIP1, HIST1H2AL, HIST1H2BG, HIST1H4D, HOXA13, HOXD13, IRX6, ITGA4, ITGB1BP3 (NMRK2), JAK3, KALRN, KIAA1549, KIAA1804, KLHL6, LAMA4, LCK, MAFB, MAP2K3, MAP7, MCHR1, MED1, MED12L, MEF2C, MSH2, MTOR, MTUS2, MUC2, MYH11, MYO18B, MYO1B, NEK2, NEURL4, NFE2L2, NTRK1, NUAK1, NUP98, ODF4, OFD1, PABPC1, PAX8, PCDH18, PDCD6, PDHB, PIK3R5, PKD1L2, PLB1, PMS2, PNN, PNPLA7, PRF1, PROKR2, PTEN, PTPN12, RAC1, RALGDS, RET, RIPK1, RNF103, RUFY1, RUNX1, SATB2, SDHB, SDHD, SHANK1, SLC25A48, SMARCA4, SSX1, STAT6, SYK, TET3, TGFBR2, TLX3, TNFRSF17, TNFSF8, TPM3, TRAK1, TRIM33, TRPS1, TRPV6, U2AF1, U2AF2, UBE2A, UBE2D1, VANGL1, VTI1A, ZFX, ZNF765.
Out of 1661 Hypomethylated genes, 288 were cancer-related genes:ABCA7, ABL1, ABLIM2, ACD, AHNAK, AJAP1, ALOX12, ALS2CL, ANGPT1, ANK3, ANKLE2, ANKRD24, APOBEC2, ARHGAP28, ASPSCR1, ATP10A, ATP2A2, ATP2B3, ATP2C2, ATRX, AXIN1, BCL2L10, BCL7A, BCOR, BRD3, BTG2, C10ORF2, C19ORF26, C1QL2, C21ORF29 (TSPEAR), C2CD4C, C3, CACNA1H, CARS, CBFA2T3, CCDC6, CCDC63, CCDC81, CCND1, CCNL1, CCT8L2, CD79B, CDC42BPB, CDC73, CDK13, CDKN1A, CDYL, CHD3, CHD4, CHD7, CHST1, CLK3, CNGA4, CNTNAP1, COL4A2, COL5A1, COL9A2, COX6C, CREBBP, CRLF2, CRTC1, CRTC3, CSMD3, CSNK2B, CTNNA2, CYFIP1, CYP2E1, CYTSB (SPECC1), DCAF12L2, DCHS1, DCTN1, DDB2, DDX41, DICER1, DIP2C, DLC1, DLEU2, DNMT1, DOT1L, DPP6, DRD5, DST, EGFLAM, EGFR, EIF3A, ELN, EPHB4, ERCC2, ERCC6, ESPL1, ETV5, EVPL, EXOC2, EYS, F8, FAM22A (NUTM2A), FAM46C, FAM58A, FAT4, FGFR2, FGFR3, FGFR4, FLCN, FLI1, FLT1, FOXO1, FOXO3, FRMD7, FTCD, FYN, GATA2, GLIPR2, GML, GNAT1, GPR123, HCN1, HDAC9, HERC2, HIST1H3D, HLF, HOXA7, HOXA9, HPD, HSP90AA1, IDH2, IGF2, IGF2R, IKZF1, IL1B, IRF2, IRF4, JAK2, KCNJ5, KDM2B, KDM5C, KDSR, KEAP1, KHSRP, KIAA0427 (CTIF), KIAA1751 (CFAP74), KIF1B, KLF2, KLHDC4, KNDC1, LDB1, LETM1, LIFR, LMX1A, LPHN1, LTK, MAFA, MAP2K2, MED12, MEN1, MLL (KMT2A), MLLT1, MLLT6, MMP13, MNX1, MSN, MSR1, MST1, MST1R, MUC6, MYCL1 (MYCL), MYD88, MYH9, MYO1G, MYOM2, NCOR2, NEUROG2, NF2, NIN, NLRP3, NOTCH1, NOTCH3, NR4A3, NRG2, NSD1, NUDT14, ODZ2 (TENM2), OLIG2, OR2A42, OR51I2, P2RY8, PAG1, PAX5, PBX1, PCDHB6, PCSK6, PCSK7, PDE4DIP, PDGFRA, PDGFRB, PDZD2, PFKP, PHC2, PHOX2B, PI4KA, PIK3AP1, PIK3CG, PIK3R1, PLCG1, PLCH2, POLE, POU5F1, PPARG, PPM1D, PPP1R3A, PPP6R2, PRDM16, PRIC285 (HELZ2), PRKX, PROM1, PTPN14, PTPRB, PTPRD, PXDN, RADIL, RASGEF1A, RBMX, RFTN1, RGS12, RHOB, RHOH, RNF213, RNF43, RPL5, RPTOR, RUNDC2A (SNX29), RXRA, RYR1, SALL3, SCN11A, SCN5A, SDHAF2, SEMA5B, SEPT7P2, SETBP1, SH3GL1, SIGLEC1, SMC3, SORCS2, SOX9, SPTBN4, SRCAP, SS18L1, ST6GAL2, STC1, STK11, STK19, SYNE2, TAL2, TBX18, TCF3, TCHH, TERT, TFDP1, TFPT, TLL2, TLR2, TMEM132D, TMPRSS2, TMSL3 (TMSB4XP8), TNFRSF14, TOP1, TP53, TRAF5, TRAF7, TRRAP, TSC2, TTC18 (CFAP70), TUBA3C, WAS, WDR24, WHSC1, WIF1, WIPF2, WT1, XPA, XPC, ZFR2, ZMYND10, ZNF331, ZNF469, ZNF497, ZNF536, ZZEF1.
Table 5

Integrative analysis of DNA methylation and gene expression at 24 h of resveratrol exposure.

Gene nameFold changePeak valueGen expression/ Methylation status
AURKA−1,861,24Low/hypermethylated
CCNB1−1,541,56Low/hypermethylated
DDIT4−2,821,8Low/hypermethylated
DLGAP5−1,571,63Low/hypermethylated
EYS−1,621,59Low/hypermethylated
FAM83D−1,521,33Low/hypermethylated
HIST1H2BK−1,521,62Low/hypermethylated
HIST1H2BM−6,631,29Low/hypermethylated
IL24−2,841,49Low/hypermethylated
LPXN−1,521,88Low/hypermethylated
NFIL3−1,51,47Low/hypermethylated
PFKFB3−1,651,5Low/hypermethylated
SLC14A1−1,681,24Low/hypermethylated
STC1−1,691,2Low/hypermethylated
AMY1A1,56−1,31High/hypomethylated
IL181,55−1,12High/hypomethylated
PEG101,61−1,42High/hypomethylated
SLIT32,13−1,34High/hypomethylated
TTI11,59−1,65High/hypomethylated
WDR521,65−1,17High/hypomethylated
Table 6

Integrative analysis of DNA methylation and gene expression at 48 h of resveratrol exposure.

Gene nameFold changePeakGen expression/ Methylation status
GPR110−2,251,1063Low/hypermethylated
HIST1H3F−1,651,5632Low/hypermethylated
HK2−2,031,0942Low/hypermethylated
MMP9−1,611,7961Low/hypermethylated
NEDD4−1,51,1856Low/hypermethylated
NFIL3−1,51,3398Low/hypermethylated
PSMD11−1,541,5088Low/hypermethylated
RUNX2−1,541,3272Low/hypermethylated
SH3KBP1−1,551,487Low/hypermethylated
ANKRD20A32,14−0,1High/hypomethylated
MPHOSPH91,56−0,39High/hypomethylated
PEG102,1−0,9High/hypomethylated
SLC27A21,56−0,26High/hypomethylated
SLIT31,88−0,12High/hypomethylated
TMOD21,56−0,19High/hypomethylated
TTI11,75−0,27High/hypomethylated
XYLB1,51−0,35High/hypomethylated

Experimental design, materials and methods

Genome-wide analysis of DNA methylation

High molecular weight DNA from MDA-MB-231 triple negative breast cancer cell line untreated and treated with resveratrol (100 µM) at 24 h and 48 h was extracted using the DNeasyKit (Qiagen, Germany) according to the manufacturer׳s instructions. For detection of the methylation status of CpG islands (CGIs), we used array-based profiling of reference-independent methylation status (aPRIMES) technology in MDA-MB-231 cells untreated and treated with resveratrol at 24 h and 48 h. This method is based on the differential restriction and competitive hybridization of methylated and unmethylated DNA by methylation-specific and methylation-sensitive restriction enzymes, and NimbleGen HG18 Refseq Promoter 3×720 K array to measure the differential DNA methylation as described in Fig. 1. Briefly, genomic DNA (500 ng) was restricted with MseI enzyme (New England Biolabs) and ligated to adapter primers according to the recommendations of the supplier. Then, one-half of the ligated MseI fragments were digested with the methylation-sensitive restriction enzymes HpaII and BstUI to cut unmethylated CGIs, and the remaining half is digested with the methylation-specific enzyme McrBC to cut CGIs methylated. Restricted samples were then subjected to 20 cycles of linker-mediated PCR, differentially labeled with fluorescent dyes Cy3 and Cy5, and competitively hybridized to a NimbleGen HG18 Refseq Promoter 3×720 K array following the conditions recommended by the supplier. DNA methylation analysis raw data was normalized and differential intensity of each probe compared with experimental IP sample (IP) and control input sample (input) was calculated using the NimbleGen software DEVA. Average fold change (IP versus input) each 50 bp bin for a range of 2.44 kb upstream and 610 bp downstream window from RefSeq transcription start sites (TSS). The methylation peak values were mapped to features using DEVA software. Regions showing enrichment at 4 or more consecutive loci were integrated together to form a single “peak”. Clusters of enriched regions separated by more than 500 base pairs were integrated as separate peaks, which reflected the probability of methylation for the designated peak and/or gene at a p-value of less than 0.01. The functional annotation of target genes based on Gene Ontology was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery).

Raw data processing and statistical analysis

A two way ANOVA was performed to identify differentially methylated genes. Only genes with statistically significant differences in DNA methylation levels (p-value <0.05) were included.
Subject areaBiology
More specific subject areaBreast cancer, Epigenetics
Type of dataTables, figure, raw data on DNA methylation (peak scores)
How data was acquiredArray-PRIMES method (aPRIMES).
NimbleGen HG18 Refseq Promoter 3×720 K arrays.
Data formatFiltered for peak annotation, and analyzed for differential enrichment and gene ontology
Experimental factorsDNA from untreated and treated MDA-MB-231 cells with resveratrol (100 µM) at 24 h and 48 h was extracted using the DNeasy Kit (Qiagen, Germany). To identify methylated and unmethylated DNA regions in the promoters of genes, we used Array-PRIMES method (aPRIMES).
Experimental featuresMDA-MB-231 cells were treated with resveratrol for 24 h and 48 h. For DNA methylation analysis we used NimbleGen HG18 Refseq Promoter 3×720 K array. The array covering 30,848 transcripts, 22,532 promoters, and 27,728 CpG islands.
Data source locationOncogenomics and Cancer Proteomics Laboratory, UACM. México City, México.
Data accessibilityData is available with this article.
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