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LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription

Oncogene volume 29, pages 3691–3702 (2010)Cite this article

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Abstract

Myc is a transcription factor that significantly contributes to cancer progression by modulating the expression of important genes through binding to a DNA sequence, CACGTG, called E-box. We find that on Myc binding to chromatin, the lysine-demethylating enzyme, LSD1, triggers a transient demethylation of lysine 4 in the histone H3. In addition, we demonstrate that Myc binds and recruits LSD1 to the E-box chromatin and the formation of this complex is stimulated by cAMP-PKA. Demethylation by LSD1 produces H2O2, which locally oxidizes guanine and induces the recruitment of 8-oxoguanine–DNA glycosylase (OGG1) and of the nuclease Ape1 on the E-box chromatin. Inhibition of oxidation or silencing of LSD1, OGG1 or Ape1 significantly reduce transcription and inhibit mRNA accumulation of Myc-target genes. Collectively, these data highlight the role of transient LSD1-mediated demethylation of H3K4 leading to local DNA oxidation as driving force in the assembly of the Myc-induced transcription initiation complex.

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References

  • Anand R, Marmorstein R . (2007). Structure and mechanism of lysine-specific demethylase enzymes. J Biol Chem 282: 35425–35429.

    Article  CAS  Google Scholar 

  • Berger SL . (2007). The complex language of chromatin regulation during transcription. Nature 447: 407–412.

    Article  CAS  Google Scholar 

  • Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S . (2003a). Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. EMBO J 22: 6299–6309.

    Article  CAS  Google Scholar 

  • Bhakat KK, Mantha AK, Mitra S . (2008). Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. Antioxid Redox Signal 11: 621–638.

    Article  Google Scholar 

  • Bhakat KK, Yang SH, Mitra S . (2003b). Acetylation of human AP-endonuclease 1, a critical enzyme in DNA repair and transcription regulation. Methods Enzymol 371: 292–300.

    Article  CAS  Google Scholar 

  • Chattopadhyay R, Das S, Maiti AK, Boldogh I, Xie J, Hazra TK et al. (2008). Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-mediated activation of the multidrug resistance gene MDR1. Mol Cell Biol 28: 7066–7080.

    Article  CAS  Google Scholar 

  • Chen D, Lucey MJ, Phoenix F, Lopez-Garcia J, Hart SM, Losson R et al. (2003). T:G mismatch-specific thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha. J Biol Chem 278: 38586–38592.

    Article  CAS  Google Scholar 

  • 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: 1115–1140.

    Article  CAS  Google Scholar 

  • Cowling VH, Cole MD . (2006). Mechanism of transcriptional activation by the Myc oncoproteins. Semin Cancer Biol 16: 242–252.

    Article  CAS  Google Scholar 

  • Eilers M, Eisenman RN . (2008). Myc's broad reach. Genes Dev 22: 2755–2766.

    Article  CAS  Google Scholar 

  • Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J et al. (2003). Genomic targets of the human c-Myc protein. Genes Dev 17: 1115–1129.

    Article  CAS  Google Scholar 

  • Forneris F, Binda C, Battaglioli E, Mattevi A . (2008). LSD1: oxidative chemistry for multifaceted functions in chromatin regulation. Trends Biochem Sci 33: 181–189.

    Article  CAS  Google Scholar 

  • Forneris F, Binda C, Vanoni MA, Mattevi A, Battaglioli E . (2005). Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process. FEBS Lett 579: 2203–2207.

    Article  CAS  Google Scholar 

  • Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan HM et al. (2003). MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep 4: 575–580.

    Article  CAS  Google Scholar 

  • Frank SR, Schroeder M, Fernandez P, Taubert S, Amati B . (2001). Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev 15: 2069–2082.

    Article  CAS  Google Scholar 

  • Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS et al. (2007). Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128: 505–518.

    Article  CAS  Google Scholar 

  • Gargano B, Amente S, Majello B, Lania L . (2007). P-TEFb is a crucial co-factor for Myc transactivation. Cell Cycle 6: 2031–2037.

    Article  CAS  Google Scholar 

  • Guccione E, Martinato F, Finocchiaro G, Luzi L, Tizzoni L, Dall' Olio V et al. (2006). Myc-binding-site recognition in the human genome is determined by chromatin context. Nat Cell Biol 8: 764–770.

    Article  CAS  Google Scholar 

  • Kim MS, Kondo T, Takada I, Youn MY, Yamamoto Y, Takahashi S et al. (2009). DNA demethylation in hormone-induced transcriptional derepression. Nature 461: 1007–1012.

    Article  CAS  Google Scholar 

  • Kirmizis A, Santos-Rosa H, Penkett CJ, Singer MA, Green RD, Kouzarides T . (2009). Distinct transcriptional outputs associated with mono- and dimethylated histone H3 arginine 2. Nat Struct Mol Biol 16: 449–451.

    Article  CAS  Google Scholar 

  • Kouzarides T . (2007). Chromatin modifications and their function. Cell 128: 693–705.

    Article  CAS  Google Scholar 

  • Lan F, Nottke AC, Shi Y . (2008). Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol 20: 316–325.

    Article  CAS  Google Scholar 

  • Littlewood TD, Hancock DC, Danielian PS, Parker MG, Evan GI . (1995). A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res 23: 1686–1690.

    Article  CAS  Google Scholar 

  • Mantha AK, Oezguen N, Bhakat KK, Izumi T, Braun W, Mitra S . (2008). Unusual role of a cysteine residue in substrate binding and activity of human AP-endonuclease 1. J Mol Biol 379: 28–37.

    Article  CAS  Google Scholar 

  • Martinato F, Cesaroni M, Amati B, Guccione E . (2008). Analysis of Myc-induced histone modifications on target chromatin. PLoS ONE 3: e3650.

    Article  Google Scholar 

  • McMahon SB, Wood MA, Cole MD . (2000). The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 20: 556–562.

    Article  CAS  Google Scholar 

  • Metzger E, Schule R . (2007). The expanding world of histone lysine demethylases. Nat Struct Mol Biol 14: 252–254.

    Article  CAS  Google Scholar 

  • Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH et al. (2005). LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437: 436–439.

    Article  CAS  Google Scholar 

  • Meyer N, Penn LZ . (2008). Reflecting on 25 years with MYC. Nat Rev Cancer 8: 976–990.

    Article  CAS  Google Scholar 

  • Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P et al. (2006). Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127: 635–648.

    Article  CAS  Google Scholar 

  • Perillo B, Ombra MN, Bertoni A, Cuozzo C, Sacchetti S, Sasso A et al. (2008). DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science 319: 202–206.

    Article  CAS  Google Scholar 

  • Schlosser I, Holzel M, Hoffmann R, Burtscher H, Kohlhuber F, Schuhmacher M et al. (2005). Dissection of transcriptional programmes in response to serum and c-Myc in a human B-cell line. Oncogene 24: 520–524.

    Article  CAS  Google Scholar 

  • Secombe J, Li L, Carlos L, Eisenman RN . (2007). The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev 21: 537–551.

    Article  CAS  Google Scholar 

  • Shi Y . (2007). Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8: 829–833.

    Article  CAS  Google Scholar 

  • Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA et al. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119: 941–953.

    Article  CAS  Google Scholar 

  • Sidorenko VS, Nevinsky GA, Zharkov DO . (2007). Mechanism of interaction between human 8-oxoguanine-DNA glycosylase and AP endonuclease. DNA Repair (Amst) 6: 317–328.

    Article  CAS  Google Scholar 

  • Tell G, Quadrifoglio F, Tiribelli C, Kelley MR . (2008). The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxid Redox Signal 11: 601–620.

    Article  Google Scholar 

  • Vervoorts J, Luscher-Firzlaff JM, Rottmann S, Lilischkis R, Walsemann G, Dohmann K et al. (2003). Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep 4: 484–490.

    Article  CAS  Google Scholar 

  • Wissmann M, Yin N, Muller JM, Greschik H, Fodor BD, Jenuwein T et al. (2007). Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol 9: 347–353.

    Article  CAS  Google Scholar 

  • Wu K-J, Mattioli M, Morse HC, Dalla Favera R . (2002). c-Myc activates protein kinase A (PKA) by direct transcriptional activation of the PKA catalytic subunit beta (PKA-Cβ) gene. Oncogene 21: 7872–7882.

    Article  CAS  Google Scholar 

  • Zeller KI, Zhao X, Lee CW, Chiu KP, Yao F, Yustein JT et al. (2006). Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci USA 103: 17834–17839.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R Dalla Favera for critical reading of the paper and A Fusco for stimulating discussions and support. This work was supported by grants from the Italian Association for Cancer Research (AIRC) and by a core grant to NOGEC (AIRC). SA is a recipient of a postdoctoral fellowship from AIRC.

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Authors and Affiliations

  1. Department of Structural and Functional Biology, University of Naples ‘Federico II’, Naples, Italy

    S Amente, L Lania & B Majello

  2. Naples Oncogenomic Center (CEINGE), Naples, Italy

    S Amente, L Lania & E V Avvedimento

  3. Department of Biology, Cellular and Molecular Pathology, ‘L. Califano’ University of Naples ‘Federico II’, Naples, Italy

    A Bertoni, A Morano & E V Avvedimento

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  1. S Amente
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  2. A Bertoni
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  3. A Morano
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  4. L Lania
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Correspondence to B Majello.

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Amente, S., Bertoni, A., Morano, A. et al. LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription. Oncogene 29, 3691–3702 (2010). https://doi.org/10.1038/onc.2010.120

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