Histone methylation modifiers in cellular signaling pathways

Abstract

Histone methyltransferases and demethylases epigenetically regulate gene expression by modifying histone methylation status in numerous cellular processes, including cell differentiation and proliferation. These modifiers also control methylation levels of various non-histone proteins, such as effector proteins that play critical roles in cellular signaling networks. Dysregulated histone methylation modifiers alter expression of oncogenes and tumor suppressor genes and change methylation states of effector proteins, frequently resulting in aberrant cellular signaling cascades and cellular transformation. In this review, we summarize the role of histone methylation modifiers in regulating the following signaling pathways: NF-κB, RAS/RAF/MEK/MAPK, PI3K/Akt, Wnt/β-catenin, p53, and ERα.

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References

  1. 1.

    Grillo MA, Colombatto S (2005) S-adenosylmethionine and protein methylation. Amino Acids 28(4):357–362. doi:10.1007/s00726-005-0197-6

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Aletta JM, Cimato TR, Ettinger MJ (1998) Protein methylation: a signal event in post-translational modification. Trends Biochem Sci 23(3):89–91

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Stallcup MR (2001) Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene 20(24):3014–3020. doi:10.1038/sj.onc.1204325

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Sprung R, Chen Y, Zhang K, Cheng D, Zhang T, Peng J, Zhao Y (2008) Identification and validation of eukaryotic aspartate and glutamate methylation in proteins. J Proteome Res 7(3):1001–1006. doi:10.1021/pr0705338

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  5. 5.

    Ng SS, Yue WW, Oppermann U, Klose RJ (2009) Dynamic protein methylation in chromatin biology. Cell Mol Life Sci 66(3):407–422. doi:10.1007/s00018-008-8303-z

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  6. 6.

    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45. doi:10.1038/47412

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Garcia BA, Hake SB, Diaz RL, Kauer M, Morris SA, Recht J, Shabanowitz J, Mishra N, Strahl BD, Allis CD, Hunt DF (2007) Organismal differences in post-translational modifications in histones H3 and H4. J Biol Chem 282(10):7641–7655. doi:10.1074/jbc.M607900200

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Cavalli G (2006) Chromatin and epigenetics in development: blending cellular memory with cell fate plasticity. Development 133(11):2089–2094. doi:10.1242/dev.02402

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Minard ME, Jain AK, Barton MC (2009) Analysis of epigenetic alterations to chromatin during development. Genesis 47(8):559–572. doi:10.1002/dvg.20534

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  10. 10.

    Briggs SD, Xiao T, Sun ZW, Caldwell JA, Shabanowitz J, Hunt DF, Allis CD, Strahl BD (2002) Gene silencing: trans-histone regulatory pathway in chromatin. Nature 418(6897):498. doi:10.1038/nature00970

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Frederiks F, Tzouros M, Oudgenoeg G, van Welsem T, Fornerod M, Krijgsveld J, van Leeuwen F (2008) Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. Nat Struct Mol Biol 15(6):550–557. doi:10.1038/nsmb.1432

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Margueron R, Trojer P, Reinberg D (2005) The key to development: interpreting the histone code? Curr Opin Genet Dev 15(2):163–176. doi:10.1016/j.gde.2005.01.005

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Pokholok DK, Harbison CT, Levine S, Cole M, Hannett NM, Lee TI, Bell GW, Walker K, Rolfe PA, Herbolsheimer E, Zeitlinger J, Lewitter F, Gifford DK, Young RA (2005) Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122(4):517–527. doi:10.1016/j.cell.2005.06.026

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Kouzarides T (2002) Histone methylation in transcriptional control. Curr Opin Genet Dev 12(2):198–209

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14(14):R546–R551. doi:10.1016/j.cub.2004.07.007

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Xu C, Henry PA, Setya A, Henry MF (2003) In vivo analysis of nucleolar proteins modified by the yeast arginine methyltransferase Hmt1/Rmt1p. RNA 9(6):746–759

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  17. 17.

    Yang Y, Bedford MT (2013) Protein arginine methyltransferases and cancer. Nat Rev Cancer 13(1):37–50. doi:10.1038/nrc3409

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Bedford MT (2007) Arginine methylation at a glance. J Cell Sci 120(Pt 24):4243–4246. doi:10.1242/jcs.019885

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Tripsianes K, Madl T, Machyna M, Fessas D, Englbrecht C, Fischer U, Neugebauer KM, Sattler M (2011) Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins. Nat Struct Mol Biol 18(12):1414–1420. doi:10.1038/nsmb.2185

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33(1):1–13. doi:10.1016/j.molcel.2008.12.013

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  21. 21.

    Bedford MT, Richard S (2005) Arginine methylation an emerging regulator of protein function. Mol Cell 18(3):263–272. doi:10.1016/j.molcel.2005.04.003

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406(6796):593–599. doi:10.1038/35020506

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Jenuwein T, Laible G, Dorn R, Reuter G (1998) SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell Mol Life Sci 54(1):80–93

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Singer MS, Kahana A, Wolf AJ, Meisinger LL, Peterson SE, Goggin C, Mahowald M, Gottschling DE (1998) Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics 150(2):613–632

    PubMed Central  CAS  PubMed  Google Scholar 

  25. 25.

    Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6(8):227. doi:10.1186/gb-2005-6-8-227

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  26. 26.

    Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y (2002) Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol 12(12):1052–1058

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Gary JD, Clarke S (1998) RNA and protein interactions modulated by protein arginine methylation. Prog Nucleic Acid Res Mol Biol 61:65–131

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Yang Y, Hadjikyriacou A, Xia Z, Gayatri S, Kim D, Zurita-Lopez C, Kelly R, Guo A, Li W, Clarke SG, Bedford MT (2015) PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145. Nat Commun 6:6428. doi:10.1038/ncomms7428

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  29. 29.

    Dhar SS, Lee SH, Kan PY, Voigt P, Ma L, Shi X, Reinberg D, Lee MG (2012) Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4. Genes Dev 26(24):2749–2762. doi:10.1101/gad.203356.112

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  30. 30.

    Lee JH, Cook JR, Yang ZH, Mirochnitchenko O, Gunderson SI, Felix AM, Herth N, Hoffmann R, Pestka S (2005) PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J Biol Chem 280(5):3656–3664. doi:10.1074/jbc.M405295200

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Karkhanis V, Wang L, Tae S, Hu YJ, Imbalzano AN, Sif S (2012) Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase delta catalytic subunit gene, POLD1. J Biol Chem 287(35):29801–29814. doi:10.1074/jbc.M112.378281

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  32. 32.

    Jelinic P, Stehle JC, Shaw P (2006) The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation. PLoS Biol 4(11):e355. doi:10.1371/journal.pbio.0040355

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  33. 33.

    Boffa LC, Karn J, Vidali G, Allfrey VG (1977) Distribution of NG, NG,-dimethylarginine in nuclear protein fractions. Biochem Biophys Res Commun 74(3):969–976

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Cheng D, Cote J, Shaaban S, Bedford MT (2007) The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol Cell 25(1):71–83. doi:10.1016/j.molcel.2006.11.019

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Branscombe TL, Frankel A, Lee JH, Cook JR, Yang Z, Pestka S, Clarke S (2001) PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins. J Biol Chem 276(35):32971–32976. doi:10.1074/jbc.M105412200

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Wolf SS (2009) The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans. Cell Mol Life Sci 66(13):2109–2121. doi:10.1007/s00018-009-0010-x

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Gayatri S, Bedford MT (2014) Readers of histone methylarginine marks. Biochim Biophys Acta 1839(8):702–710. doi:10.1016/j.bbagrm.2014.02.015

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  38. 38.

    Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119(7):941–953. doi:10.1016/j.cell.2004.12.012

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Lee MG, Wynder C, Cooch N, Shiekhattar R (2005) An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437(7057):432–435. doi:10.1038/nature04021

    CAS  PubMed  Google Scholar 

  40. 40.

    Klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8(4):307–318. doi:10.1038/nrm2143

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439(7078):811–816. doi:10.1038/nature04433

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125(3):467–481. doi:10.1016/j.cell.2006.03.028

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Mosammaparast N, Shi Y (2010) Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem 79:155–179. doi:10.1146/annurev.biochem.78.070907.103946

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Cloos PA, Christensen J, Agger K, Helin K (2008) Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev 22(9):1115–1140. doi:10.1101/gad.1652908

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  45. 45.

    Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21(3):381–395. doi:10.1038/cr.2011.22

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  46. 46.

    Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase. Science 318(5849):444–447. doi:10.1126/science.1145801

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Liu W, Ma Q, Wong K, Li W, Ohgi K, Zhang J, Aggarwal AK, Rosenfeld MG (2013) Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell 155(7):1581–1595. doi:10.1016/j.cell.2013.10.056

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  48. 48.

    Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C, Butler DS, Yates JR 3rd, Delahunty CM, Hahn P, Lengeling A, Mann M, Proudfoot NJ, Schofield CJ, Bottger A (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325(5936):90–93. doi:10.1126/science.1175865

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Feinberg AP, Oshimura M, Barrett JC (2002) Epigenetic mechanisms in human disease. Cancer Res 62(22):6784–6787

    CAS  PubMed  Google Scholar 

  50. 50.

    Handel AE, Ebers GC, Ramagopalan SV (2010) Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med 16(1):7–16. doi:10.1016/j.molmed.2009.11.003

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18(18):2195–2224. doi:10.1101/gad.1228704

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Bharti AC, Aggarwal BB (2002) Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 64(5–6):883–888

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Basseres DS, Baldwin AS (2006) Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene 25(51):6817–6830. doi:10.1038/sj.onc.1209942

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436. doi:10.1038/nature04870

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Perkins ND (2006) Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 25(51):6717–6730. doi:10.1038/sj.onc.1209937

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, Gudkov AV, Stark GR (2010) Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci USA 107(1):46–51. doi:10.1073/pnas.0912493107

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  58. 58.

    Zhang T, Park KA, Li Y, Byun HS, Jeon J, Lee Y, Hong JH, Kim JM, Huang SM, Choi SW, Kim SH, Sohn KC, Ro H, Lee JH, Lu T, Stark GR, Shen HM, Liu ZG, Park J, Hur GM (2013) PHF20 regulates NF-kappaB signalling by disrupting recruitment of PP2A to p65. Nat Commun 4:2062. doi:10.1038/ncomms3062

    PubMed Central  PubMed  Google Scholar 

  59. 59.

    Ea CK, Baltimore D (2009) Regulation of NF-kappaB activity through lysine monomethylation of p65. Proc Natl Acad Sci USA 106(45):18972–18977. doi:10.1073/pnas.0910439106

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  60. 60.

    Nishioka K, Chuikov S, Sarma K, Erdjument-Bromage H, Allis CD, Tempst P, Reinberg D (2002) Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Genes Dev 16(4):479–489. doi:10.1101/gad.967202

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  61. 61.

    Wang H, Cao R, Xia L, Erdjument-Bromage H, Borchers C, Tempst P, Zhang Y (2001) Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol Cell 8(6):1207–1217

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ, Barlev NA, Reinberg D (2004) Regulation of p53 activity through lysine methylation. Nature 432(7015):353–360. doi:10.1038/nature03117

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Lu T, Yang M, Huang DB, Wei H, Ozer GH, Ghosh G, Stark GR (2013) Role of lysine methylation of NF-kappaB in differential gene regulation. Proc Natl Acad Sci USA 110(33):13510–13515. doi:10.1073/pnas.1311770110

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  64. 64.

    Yang XD, Huang B, Li M, Lamb A, Kelleher NL, Chen LF (2009) Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit. EMBO J 28(8):1055–1066. doi:10.1038/emboj.2009.55

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  65. 65.

    Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O (2011) Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. Nat Immunol 12(1):29–36. doi:10.1038/ni.1968

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  66. 66.

    Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang DB, Ghosh G, Stark GR, Lu T (2013) PRMT5 dimethylates R30 of the p65 subunit to activate NF-kappaB. Proc Natl Acad Sci USA 110(33):13516–13521. doi:10.1073/pnas.1311784110

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  67. 67.

    Wei H, Mundade R, Lange KC, Lu T (2014) Protein arginine methylation of non-histone proteins and its role in diseases. Cell Cycle 13(1):32–41. doi:10.4161/cc.27353

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  68. 68.

    Yang P, Guo L, Duan ZJ, Tepper CG, Xue L, Chen X, Kung HJ, Gao AC, Zou JX, Chen HW (2012) Histone methyltransferase NSD2/MMSET mediates constitutive NF-kappaB signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. Mol Cell Biol 32(15):3121–3131. doi:10.1128/MCB.00204-12

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  69. 69.

    Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, Liou YC, Yu Q (2011) Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell 43(5):798–810. doi:10.1016/j.molcel.2011.08.011

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Chen X, El Gazzar M, Yoza BK, McCall CE (2009) The NF-kappaB factor RelB and histone H3 lysine methyltransferase G9a directly interact to generate epigenetic silencing in endotoxin tolerance. J Biol Chem 284(41):27857–27865. doi:10.1074/jbc.M109.000950

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  71. 71.

    Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26(22):3279–3290. doi:10.1038/sj.onc.1210421

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH (2001) MAP kinases. Chem Rev 101(8):2449–2476

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81(2):807–869

    CAS  PubMed  Google Scholar 

  74. 74.

    Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22(2):153–183. doi:10.1210/edrv.22.2.0428

    CAS  PubMed  Google Scholar 

  75. 75.

    Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75(1):50–83. doi:10.1128/MMBR.00031-10

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  76. 76.

    Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, Lee HJ, Wang YN, Liu M, Liao HW, Shi B, Lai CC, Bedford MT, Tsai CH, Hung MC (2011) Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol 13(2):174–181. doi:10.1038/ncb2158

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  77. 77.

    Andreu-Perez P, Esteve-Puig R, de Torre-Minguela C, Lopez-Fauqued M, Bech-Serra JJ, Tenbaum S, Garcia-Trevijano ER, Canals F, Merlino G, Avila MA, Recio JA (2011) Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal 4(190):ra58. doi:10.1126/scisignal.2001936

  78. 78.

    Wei TY, Juan CC, Hisa JY, Su LJ, Lee YC, Chou HY, Chen JM, Wu YC, Chiu SC, Hsu CP, Liu KL, Yu CT (2012) Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. Cancer Sci 103(9):1640–1650. doi:10.1111/j.1349-7006.2012.02367.x

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Wang L, Pal S, Sif S (2008) Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells. Mol Cell Biol 28(20):6262–6277. doi:10.1128/MCB.00923-08

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  80. 80.

    Van Aller GS, Reynoird N, Barbash O, Huddleston M, Liu S, Zmoos AF, McDevitt P, Sinnamon R, Le B, Mas G, Annan R, Sage J, Garcia BA, Tummino PJ, Gozani O, Kruger RG (2012) Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics 7(4):340–343. doi:10.4161/epi.19506

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  81. 81.

    Mazur PK, Reynoird N, Khatri P, Jansen PW, Wilkinson AW, Liu S, Barbash O, Van Aller GS, Huddleston M, Dhanak D, Tummino PJ, Kruger RG, Garcia BA, Butte AJ, Vermeulen M, Sage J, Gozani O (2014) SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510(7504):283–287. doi:10.1038/nature13320

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  82. 82.

    Wagner KW, Alam H, Dhar SS, Giri U, Li N, Wei Y, Giri D, Cascone T, Kim JH, Ye Y, Multani AS, Chan CH, Erez B, Saigal B, Chung J, Lin HK, Wu X, Hung MC, Heymach JV, Lee MG (2013) KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest 123(12):5231–5246. doi:10.1172/JCI68642

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  83. 83.

    Chen H, Kluz T, Zhang R, Costa M (2010) Hypoxia and nickel inhibit histone demethylase JMJD1A and repress Spry2 expression in human bronchial epithelial BEAS-2B cells. Carcinogenesis 31(12):2136–2144. doi:10.1093/carcin/bgq197

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  84. 84.

    Chen H, Giri NC, Zhang R, Yamane K, Zhang Y, Maroney M, Costa M (2010) Nickel ions inhibit histone demethylase JMJD1A and DNA repair enzyme ABH2 by replacing the ferrous iron in the catalytic centers. J Biol Chem 285(10):7374–7383. doi:10.1074/jbc.M109.058503

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  85. 85.

    Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, Guney I, Strochlic DE, Macconaill LE, Beroukhim R, Bronson RT, Ryeom S, Hahn WC, Loda M, Cichowski K (2010) An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med 16(3):286–294. doi:10.1038/nm.2100

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  86. 86.

    Moore HM, Gonzalez ME, Toy KA, Cimino-Mathews A, Argani P, Kleer CG (2013) EZH2 inhibition decreases p38 signaling and suppresses breast cancer motility and metastasis. Breast Cancer Res Treat 138(3):741–752. doi:10.1007/s10549-013-2498-x

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  87. 87.

    Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501. doi:10.1038/nrc839

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Hemmings BA, Restuccia DF (2012) PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol 4(9):a011189. doi:10.1101/cshperspect.a011189

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  89. 89.

    Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274. doi:10.1016/j.cell.2007.06.009

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  90. 90.

    Testa JR, Tsichlis PN (2005) AKT signaling in normal and malignant cells. Oncogene 24(50):7391–7393. doi:10.1038/sj.onc.1209100

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Yang WL, Wu CY, Wu J, Lin HK (2010) Regulation of Akt signaling activation by ubiquitination. Cell Cycle 9(3):487–497

    PubMed Central  PubMed  Article  Google Scholar 

  92. 92.

    Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung MC, Nakayama KI, Lin HK (2012) The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 149(5):1098–1111. doi:10.1016/j.cell.2012.02.065

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  93. 93.

    de la Cruz-Herrera CF, Campagna M, Lang V, Del Carmen Gonzalez-Santamaria J, Marcos-Villar L, Rodriguez MS, Vidal A, Collado M, Rivas C (2014) SUMOylation regulates AKT1 activity. Oncogene. doi:10.1038/onc.2014.48

    Google Scholar 

  94. 94.

    Li R, Wei J, Jiang C, Liu D, Deng L, Zhang K, Wang P (2013) Akt SUMOylation regulates cell proliferation and tumorigenesis. Cancer Res 73(18):5742–5753. doi:10.1158/0008-5472.CAN-13-0538

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y, Fukamizu A (2008) Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell 32(2):221–231. doi:10.1016/j.molcel.2008.09.013

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Sakamaki J, Daitoku H, Ueno K, Hagiwara A, Yamagata K, Fukamizu A (2011) Arginine methylation of BCL-2 antagonist of cell death (BAD) counteracts its phosphorylation and inactivation by Akt. Proc Natl Acad Sci USA 108(15):6085–6090. doi:10.1073/pnas.1015328108

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  97. 97.

    Le Romancer M, Treilleux I, Leconte N, Robin-Lespinasse Y, Sentis S, Bouchekioua-Bouzaghou K, Goddard S, Gobert-Gosse S, Corbo L (2008) Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Mol Cell 31(2):212–221. doi:10.1016/j.molcel.2008.05.025

    PubMed  Article  CAS  Google Scholar 

  98. 98.

    Gonzalez ME, DuPrie ML, Krueger H, Merajver SD, Ventura AC, Toy KA, Kleer CG (2011) Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res 71(6):2360–2370. doi:10.1158/0008-5472.CAN-10-1933

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  99. 99.

    Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480. doi:10.1016/j.cell.2006.10.018

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Cadigan KM, Nusse R (1997) Wnt signaling: a common theme in animal development. Genes Dev 11(24):3286–3305

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Polakis P (2012) Drugging Wnt signalling in cancer. EMBO J 31(12):2737–2746. doi:10.1038/emboj.2012.126

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  102. 102.

    Arce L, Yokoyama NN, Waterman ML (2006) Diversity of LEF/TCF action in development and disease. Oncogene 25(57):7492–7504. doi:10.1038/sj.onc.1210056

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Mosimann C, Hausmann G, Basler K (2009) Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol 10(4):276–286. doi:10.1038/nrm2654

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN, Hung MC (2011) EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 19(1):86–100. doi:10.1016/j.ccr.2010.10.035

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  105. 105.

    Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, Hung MC (2005) Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19(2):159–170. doi:10.1016/j.molcel.2005.06.009

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Cheng AS, Lau SS, Chen Y, Kondo Y, Li MS, Feng H, Ching AK, Cheung KF, Wong HK, Tong JH, Jin H, Choy KW, Yu J, To KF, Wong N, Huang TH, Sung JJ (2011) EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res 71(11):4028–4039. doi:10.1158/0008-5472.CAN-10-3342

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Lu H, Sun J, Wang F, Feng L, Ma Y, Shen Q, Jiang Z, Sun X, Wang X, Jin H (2013) Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4. Cell Death Dis 4:e776. doi:10.1038/cddis.2013.293

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  108. 108.

    Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, Caragacianu D, Schrump DS (2009) Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res 69(8):3570–3578. doi:10.1158/0008-5472.CAN-08-2807

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Shi B, Liang J, Yang X, Wang Y, Zhao Y, Wu H, Sun L, Zhang Y, Chen Y, Li R, Zhang Y, Hong M, Shang Y (2007) Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 27(14):5105–5119. doi:10.1128/MCB.00162-07

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  110. 110.

    Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, McCrea PD, Park JI (2013) PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. Mol Cell 52(2):193–205. doi:10.1016/j.molcel.2013.08.028

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  111. 111.

    Mohan M, Herz HM, Takahashi YH, Lin C, Lai KC, Zhang Y, Washburn MP, Florens L, Shilatifard A (2010) Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev 24(6):574–589. doi:10.1101/gad.1898410

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  112. 112.

    Li Z, Nie F, Wang S, Li L (2011) Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. Proc Natl Acad Sci USA 108(8):3116–3123. doi:10.1073/pnas.1009353108

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  113. 113.

    Toyokawa G, Cho HS, Masuda K, Yamane Y, Yoshimatsu M, Hayami S, Takawa M, Iwai Y, Daigo Y, Tsuchiya E, Tsunoda T, Field HI, Kelly JD, Neal DE, Maehara Y, Ponder BA, Nakamura Y, Hamamoto R (2011) Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the Wnt pathway. Neoplasia 13(10):887–898

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  114. 114.

    Blythe SA, Cha SW, Tadjuidje E, Heasman J, Klein PS (2010) beta-Catenin primes organizer gene expression by recruiting a histone H3 arginine 8 methyltransferase, Prmt2. Dev Cell 19(2):220–231. doi:10.1016/j.devcel.2010.07.007

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  115. 115.

    Cha B, Kim W, Kim YK, Hwang BN, Park SY, Yoon JW, Park WS, Cho JW, Bedford MT, Jho EH (2011) Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling. Oncogene 30(20):2379–2389. doi:10.1038/onc.2010.610

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Appella E, Anderson CW (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268(10):2764–2772

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Lane DP (1999) Exploiting the p53 pathway for cancer diagnosis and therapy. Br J Cancer 80(Suppl 1):1–5

    CAS  PubMed  Google Scholar 

  118. 118.

    Prives C, Hall PA (1999) The p53 pathway. J Pathol 187(1):112–126. doi:10.1002/(SICI)1096-9896(199901)187:1<112:AID-PATH250>3.0.CO;2-3

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Brooks CL, Gu W (2003) Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15(2):164–171

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Momand J, Wu HH, Dasgupta G (2000) MDM2—master regulator of the p53 tumor suppressor protein. Gene 242(1–2):15–29

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Shieh SY, Ikeda M, Taya Y, Prives C (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91(3):325–334

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Zhang X, Wen H, Shi X (2012) Lysine methylation: beyond histones. Acta Biochim Biophys Sin (Shanghai) 44(1):14–27. doi:10.1093/abbs/gmr100

    Article  CAS  Google Scholar 

  123. 123.

    Huang J, Berger SL (2008) The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev 18(2):152–158. doi:10.1016/j.gde.2008.01.012

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Lan F, Shi Y (2009) Epigenetic regulation: methylation of histone and non-histone proteins. Sci China C Life Sci 52(4):311–322. doi:10.1007/s11427-009-0054-z

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    West LE, Gozani O (2011) Regulation of p53 function by lysine methylation. Epigenomics 3(3):361–369. doi:10.2217/EPI.11.21

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  126. 126.

    Ivanov GS, Ivanova T, Kurash J, Ivanov A, Chuikov S, Gizatullin F, Herrera-Medina EM, Rauscher F 3rd, Reinberg D, Barlev NA (2007) Methylation-acetylation interplay activates p53 in response to DNA damage. Mol Cell Biol 27(19):6756–6769. doi:10.1128/MCB.00460-07

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  127. 127.

    Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL (2006) Repression of p53 activity by Smyd2-mediated methylation. Nature 444(7119):629–632. doi:10.1038/nature05287

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL (2007) p53 is regulated by the lysine demethylase LSD1. Nature 449(7158):105–108. doi:10.1038/nature06092

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Iwabuchi K, Bartel PL, Li B, Marraccino R, Fields S (1994) Two cellular proteins that bind to wild-type but not mutant p53. Proc Natl Acad Sci USA 91(13):6098–6102

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  130. 130.

    Iwabuchi K, Li B, Massa HF, Trask BJ, Date T, Fields S (1998) Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2. J Biol Chem 273(40):26061–26068

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Shi X, Kachirskaia I, Yamaguchi H, West LE, Wen H, Wang EW, Dutta S, Appella E, Gozani O (2007) Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol Cell 27(4):636–646. doi:10.1016/j.molcel.2007.07.012

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  132. 132.

    Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T, Reinberg D, Berger SL (2010) G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 285(13):9636–9641. doi:10.1074/jbc.M109.062588

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  133. 133.

    Collingwood TN, Urnov FD, Wolffe AP (1999) Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription. J Mol Endocrinol 23(3):255–275

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    McDonnell DP, Norris JD (2002) Connections and regulation of the human estrogen receptor. Science 296(5573):1642–1644. doi:10.1126/science.1071884

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20(3):321–344. doi:10.1210/edrv.20.3.0366

    CAS  PubMed  Google Scholar 

  136. 136.

    Hervouet E, Cartron PF, Jouvenot M, Delage-Mourroux R (2013) Epigenetic regulation of estrogen signaling in breast cancer. Epigenetics 8(3):237–245. doi:10.4161/epi.23790

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  137. 137.

    Mann M, Cortez V, Vadlamudi RK (2011) Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy. Cancers (Basel) 3(3):1691–1707. doi:10.3390/cancers3021691

    CAS  Article  Google Scholar 

  138. 138.

    Hall JM, McDonnell DP (2005) Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv 5(6):343–357. doi:10.1124/mi.5.6.7

    PubMed  Article  Google Scholar 

  139. 139.

    Green KA, Carroll JS (2007) Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer 7(9):713–722. doi:10.1038/nrc2211

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87(3):905–931. doi:10.1152/physrev.00026.2006

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V (2010) Protein arginine methylation in estrogen signaling and estrogen-related cancers. Trends Endocrinol Metab 21(3):181–189. doi:10.1016/j.tem.2009.11.002

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Tsai MJ, O’Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63:451–486. doi:10.1146/annurev.bi.63.070194.002315

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Barnes CJ, Vadlamudi RK, Kumar R (2004) Novel estrogen receptor coregulators and signaling molecules in human diseases. Cell Mol Life Sci 61(3):281–291. doi:10.1007/s00018-003-3222-5

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Magnani L, Lupien M (2014) Chromatin and epigenetic determinants of estrogen receptor alpha (ESR1) signaling. Mol Cell Endocrinol 382(1):633–641. doi:10.1016/j.mce.2013.04.026

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Dreijerink KM, Mulder KW, Winkler GS, Hoppener JW, Lips CJ, Timmers HT (2006) Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Res 66(9):4929–4935. doi:10.1158/0008-5472.CAN-05-4461

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Ansari KI, Kasiri S, Hussain I, Mandal SS (2009) Mixed lineage leukemia histone methylases play critical roles in estrogen-mediated regulation of HOXC13. FEBS J 276(24):7400–7411. doi:10.1111/j.1742-4658.2009.07453.x

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Mo R, Rao SM, Zhu YJ (2006) Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. J Biol Chem 281(23):15714–15720. doi:10.1074/jbc.M513245200

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Kim JH, Sharma A, Dhar SS, Lee SH, Gu B, Chan CH, Lin HK, Lee MG (2014) UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. Cancer Res 74(6):1705–1717. doi:10.1158/0008-5472.CAN-13-1896

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  149. 149.

    Kim H, Heo K, Kim JH, Kim K, Choi J, An W (2009) Requirement of histone methyltransferase SMYD3 for estrogen receptor-mediated transcription. J Biol Chem 284(30):19867–19877. doi:10.1074/jbc.M109.021485

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  150. 150.

    Zhang X, Tanaka K, Yan J, Li J, Peng D, Jiang Y, Yang Z, Barton MC, Wen H, Shi X (2013) Regulation of estrogen receptor alpha by histone methyltransferase SMYD2-mediated protein methylation. Proc Natl Acad Sci USA 110(43):17284–17289. doi:10.1073/pnas.1307959110

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  151. 151.

    Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS, Ju BG, Ohgi KA, Wang J, Escoubet-Lozach L, Rose DW, Glass CK, Fu XD, Rosenfeld MG (2007) Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128(3):505–518. doi:10.1016/j.cell.2006.12.038

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  152. 152.

    Perillo B, Ombra MN, Bertoni A, Cuozzo C, Sacchetti S, Sasso A, Chiariotti L, Malorni A, Abbondanza C, Avvedimento EV (2008) DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science 319(5860):202–206. doi:10.1126/science.1147674

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M, Gannon F (2003) Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115(6):751–763

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Frietze S, Lupien M, Silver PA, Brown M (2008) CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res 68(1):301–306. doi:10.1158/0008-5472.CAN-07-1983

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Feng Q, Yi P, Wong J, O’Malley BW (2006) Signaling within a coactivator complex: methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol 26(21):7846–7857. doi:10.1128/MCB.00568-06

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  156. 156.

    Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD, Briggs SD, Allis CD, Wong J, Tempst P, Zhang Y (2001) Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293(5531):853–857. doi:10.1126/science.1060781

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Mostaqul Huq MD, Gupta P, Tsai NP, White R, Parker MG, Wei LN (2006) Suppression of receptor interacting protein 140 repressive activity by protein arginine methylation. EMBO J 25(21):5094–5104. doi:10.1038/sj.emboj.7601389

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  158. 158.

    Teyssier C, Ma H, Emter R, Kralli A, Stallcup MR (2005) Activation of nuclear receptor coactivator PGC-1alpha by arginine methylation. Genes Dev 19(12):1466–1473. doi:10.1101/gad.1295005

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  159. 159.

    Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, Loizou E, Holmfeldt L, Strikoudis A, King B, Mullenders J, Becksfort J, Nedjic J, Paietta E, Tallman MS, Rowe JM, Tonon G, Satoh T, Kruidenier L, Prinjha R, Akira S, Van Vlierberghe P, Ferrando AA, Jaenisch R, Mullighan CG, Aifantis I (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514(7523):513–517. doi:10.1038/nature13605

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  160. 160.

    Hock H (2012) A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev 26(8):751–755. doi:10.1101/gad.191163.112

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  161. 161.

    Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, Boucher G, Chagnon P, Drouin S, Lambert R, Rondeau C, Bilodeau A, Lavallee S, Sauvageau M, Hebert J, Sauvageau G (2012) A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 26(7):651–656. doi:10.1101/gad.186411.111

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  162. 162.

    McGrath J, Trojer P (2015) Targeting histone lysine methylation in cancer. Pharmacol Ther. doi:10.1016/j.pharmthera.2015.01.002

    PubMed  Google Scholar 

  163. 163.

    Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR (2005) Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci USA 102(10):3611–3616. doi:10.1073/pnas.0407159102

    PubMed Central  CAS  PubMed  Article  Google Scholar 

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Acknowledgments

We apologize for not reviewing numerous pertinent articles because of space limitations. We are thankful to Kathryn Hale for manuscript editing. The work of this laboratory is supported by grants to M.G.L. from the NIH (R01 GM095659 and R01 CA157919), the Center for Cancer Epigenetics at The University of Texas MD Anderson Cancer Center, and Cancer Prevention and Research Institute of Texas (RP110183) and by a fellowship to H.A. from the Odyssey Program at MD Anderson Cancer Center.

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Correspondence to Min Gyu Lee.

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Alam, H., Gu, B. & Lee, M.G. Histone methylation modifiers in cellular signaling pathways. Cell. Mol. Life Sci. 72, 4577–4592 (2015). https://doi.org/10.1007/s00018-015-2023-y

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Keywords

  • Histone methylation
  • Histone methyltransferase
  • Histone demethylase
  • Oncogenic signaling
  • Tumor suppressor pathway