Journal Article

Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression

Vogler, Christine, Buettner, Reinhard, Greschik, Holger, Jenuwein, Thomas, Fodor, Barna D., Günther, Thomas, Müller, Judith M., Schneider, Robert, Schüle, Roland, Wissmann, Melanie, Metzger, Eric, Yin, Na

2007

Overview

Posttranslational modifications of histones, such as methylation, regulate chromatin structure and gene expression 1 . Recently, lysine-specific demethylase 1 (LSD1) 2 , the first histone demethylase, was identified. LSD1 interacts with the androgen receptor and promotes androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9) 3 only. Here, we identify the Jumonji C (JMJC) 4 domain-containing protein JMJD2C 5 , 6 as the first histone tridemethylase regulating androgen receptor function. JMJD2C interacts with androgen receptor in vitro and in vivo . Assembly of ligand-bound androgen receptor and JMJD2C on androgen receptor-target genes results in demethylation of trimethyl H3K9 and in stimulation of androgen receptor-dependent transcription. Conversely, knockdown of JMJD2C inhibits androgen-induced removal of trimethyl H3K9, transcriptional activation and tumour cell proliferation. Importantly, JMJD2C colocalizes with androgen receptor and LSD1 in normal prostate and in prostate carcinomas. JMJD2C and LSD1 interact and both demethylases cooperatively stimulate androgen receptor-dependent gene transcription. In addition, androgen receptor, JMJD2C and LSD1 assemble on chromatin to remove methyl groups from mono, di and trimethylated H3K9. Thus, our data suggest that specific gene regulation requires the assembly and coordinate action of demethylases with distinct substrate specificities.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Androgens / Animals / Biomedical and Life Sciences / Cancer Research / Cell Biology / Cell growth / Cell Line / Cell Line, Tumor / Cell Proliferation - drug effects / Cercopithecus aethiops / Chemical properties / Developmental Biology / Evaluation / Gene expression / Gene Expression Regulation - drug effects / HeLa Cells / Histone Demethylases / Histones / Histones - metabolism / Hormone receptors / Humans / Jumonji Domain-Containing Histone Demethylases / letter / Life Sciences / Ligands / Male / Methylation / Metribolone - pharmacology / MicroRNAs - genetics / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Oxidoreductases, N-Demethylating - genetics / Oxidoreductases, N-Demethylating - metabolism / Physiological aspects / Prostate / Prostate-Specific Antigen - genetics / Prostate-Specific Antigen - metabolism / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Protein Binding - drug effects / Proteins / Receptors, Androgen - analysis / Receptors, Androgen - metabolism / Receptors, Glucocorticoid - genetics / Receptors, Glucocorticoid - metabolism / Receptors, Progesterone - genetics / Receptors, Progesterone - metabolism / Response Elements - genetics / RNA, Small Interfering - genetics / Stem Cells / Tissue Kallikreins - genetics / Transcription Factors - genetics / Transcription Factors - metabolism / Transfection