The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3

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Abstract
Two papers in this issue identify enzymes capable of demethylating a trimethyl group from the Lys 9 residue of histone H3 — a 'mark' required for the establishment of heterochromatin and previously considered stable. Cloos et al. show that GASC1, a member of the JMJD2 enzyme family, can disrupt heterochromatin structure when overexpressed and may contribute to tumour development. Klose et al. show that overexpression of JHDM3A, also a JMJD2-type enzyme, disrupts heterochromatin structure. It may function in euchromatin to regulate transcription. One of two papers in this issue that identifies enzymes capable of demethylating a tri-methyl group from Lys 9 of histone H3 — a mark required for the establishment of heterochromatin and previously considered to be stable. GASC1, a member of the JMJD2 enzyme family, can disrupt heterochromatin structure when overexpressed and may contribute to tumour development. Methylation of lysine and arginine residues on histone tails affects chromatin structure and gene transcription1,2,3. 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 species4,5,6. H3K9me3 has long been regarded as a ‘permanent’ epigenetic mark7,8. In a search for proteins and complexes interacting with H3K9me3, we identified the protein GASC1 (gene amplified in squamous cell carcinoma 1)9, which belongs to the JMJD2 (jumonji domain containing 2) subfamily of the jumonji family, and is also known as JMJD2C10. Here we show that three members of this subfamily of proteins demethylate H3K9me3/me2 in vitro through a hydroxylation reaction requiring iron and α-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 carcinomas9,11,12, 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.