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

• Published in: Oncogene Vol. 29; no. 25; pp. 3691 - 3702
• Main Authors: Amente, S, Bertoni, A, Morano, A, Lania, L, Avvedimento, E V, Majello, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-06-2010; Nature Publishing Group
• Subjects: 631/337/100/2285; 631/337/572; 631/45/607/1168; 631/67; Animals; Apoptosis; Binding sites; Biological and medical sciences; Cancer; Cell Biology; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromatin; Chromatin - genetics; Demethylation; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA damage; DNA glycosylase; DNA Repair Enzymes - metabolism; E-Box Elements; Fundamental and applied biological sciences. Psychology; Genetic aspects; Guanine; Histone Demethylases - metabolism; Histone H3; Histones; Histones - metabolism; Human Genetics; Hydrogen peroxide; Initiation complex; Internal Medicine; Lysine; Lysine - metabolism; Medicine; Medicine & Public Health; Methylation; Mitogens - pharmacology; Molecular and cellular biology; Molecular genetics; Myc protein; Nuclease; Nucleotide sequence; OGG1 protein; Oncology; original-article; Oxidation; Oxidation-Reduction; Physiological aspects; Protein kinase A; Proto-Oncogene Proteins c-myc - metabolism; Rats; Risk factors; Transcription factors; Transcription, Genetic - drug effects; Transcription. Transcription factor. Splicing. Rna processing; Italy; oxidative burst; histone; transcription; Myc; methylation; LSD1; Demethylation; Transcription; Lysine; Onc gene; Methylation; Carcinogenesis; Histone H3
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.120

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 H
2
O
2
, 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.