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

被引：137

作者：

Amente, S. ^{[1
,2
]}

Bertoni, A. ^{[3
]}

Morano, A. ^{[3
]}

Lania, L. ^{[1
,2
]}

Avvedimento, E. V. ^{[2
,3
]}

Majello, B. ^{[1
]}

机构：

[1] Univ Naples Federico II, Dept Struct & Funct Biol, I-80126 Naples, Italy

[2] Naples Oncogenom Ctr CEINGE, Naples, Italy

[3] L Califano Univ Naples Federico II, Dept Biol Cellular & Mol Pathol, Naples, Italy

来源：

ONCOGENE | 2010年 / 29卷 / 25期

关键词：

Myc; LSD1; transcription; histone; methylation; oxidative burst; AP-ENDONUCLEASE APE1/REF-1; C-MYC; BINDING; ACTIVATION; LSD1; ACETYLATION; MECHANISM; COFACTOR; GLYCOSYLASE; RECRUITS;

D O I：

10.1038/onc.2010.120

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Oncogene (2010) 29, 3691-3702; doi: 10.1038/onc.2010.120; published online 26 April 2010

引用

页码：3691 / 3702

页数：12

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