title: The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3.
abstract: Methylation of lysine and arginine residues on histone tails affects chromatin structure and gene transcription. Tri- and dimethylation of lysine 9 on histone H3 (H3K9me3/me2) is required for the binding of the repressive protein HP1 and is associated with heterochromatin formation and transcriptional repression in a variety of species. H3K9me3 has long been regarded as a 'permanent' epigenetic mark. In a search for proteins and complexes interacting with H3K9me3, we identified the protein GASC1 (gene amplified in squamous cell carcinoma 1), which belongs to the JMJD2 (jumonji domain containing 2) subfamily of the jumonji family, and is also known as JMJD2C. Here we show that three members of this subfamily of proteins demethylate H3K9me3/me2 in vitro through a hydroxylation reaction requiring iron and alpha-ketoglutarate as cofactors. Furthermore, we demonstrate that ectopic expression of GASC1 or other JMJD2 members markedly decreases H3K9me3/me2 levels, increases H3K9me1 levels, delocalizes HP1 and reduces heterochromatin in vivo. Previously, GASC1 was found to be amplified in several cell lines derived from oesophageal squamous carcinomas, and in agreement with a contribution of GASC1 to tumour development, inhibition of GASC1 expression decreases cell proliferation. Thus, in addition to identifying GASC1 as a histone trimethyl demethylase, we suggest a model for how this enzyme might be involved in cancer development, and propose it as a target for anti-cancer therapy.
authors.affiliation: Biotech Research & Innovation Centre, Fruebjergvej 3, 2100 Copenhagen, Denmark.
authors.forename: Paul A C
authors.initials: PA
authors.lastname: Cloos
authors.forename: Jesper
authors.initials: J
authors.lastname: Christensen
authors.forename: Karl
authors.initials: K
authors.lastname: Agger
authors.forename: Alessio
authors.initials: A
authors.lastname: Maiolica
authors.forename: Juri
authors.initials: J
authors.lastname: Rappsilber
authors.forename: Torben
authors.initials: T
authors.lastname: Antal
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Hansen
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
mesh_terms: D049109:Cell Proliferation; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine / Q000737:chemistry* / Q000378:metabolism*; D008745:Methylation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D011485:Protein Binding; D013379:Substrate Specificity; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C413655:KDM4C protein, human; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine