The oncogenic potential of Jumonji D2 (JMJD2/KDM4) histone demethylase overexpression

The Jumonji D2 proteins (JMJD2/KDM4) function to demethylate di- and trimethylated (me2/3) histone 3 lysine 9 (H3K9me2/3) and H3K36me3. Knockout mouse models for Kdm4b and Kdm4d have not resulted in gross abnormalities, while mouse models for Kdm4a and Kdm4c have not been reported. However, the KDM4 subfamily of demethylases are overexpressed in several tumor types. Overexpression of KDM4 proteins alters transcription and chromatin remodeling, driving cellular proliferation, anchorage-independent growth, invasion, and migration. Increased proliferation occurs through KDM4-mediated modification of cell cycle timing, as well as through increased numbers of replication forks. Recent evidence also suggests that KDM4C overexpression contributes to the maintenance of a pluripotent state. Together these data suggest that overexpression of KDM4 proteins induces numerous oncogenic effects. Key words: demethylase, H3K9me3, Jumonji, JMJD2/KDM4, cancer. Resume: Les proteines Jumonji D2 (JMJD2/KDM4) ont pour fonction de demethyler la lysine 9 de l'histone H3 di- et tri-methylee (H3K9me2/3) et la H3K36me3. Des modeles d'inactivation de kdm4b et kdm4d chez la souris ne resultent pas en anomalies majeures, alors que des modeles d'inactivation de kdm4a et kdm4c n'ont jamais ete rapportes. Cependant, la sous-famille de demethylases KDM4 est surexprimee dans plusieurs types de tumeurs. La surexpression des proteines KDM4 altere la transcription et le remodelage de la chromatine, induisant la proliferation cellulaire, la croissance independante de l'ancrage, l'invasion et la migration. Une proliferation accrue survient par l'intermediaire d'une modification du programme du cycle cellulaire dependante de KDM4 et de meme que par un nombre accru de fourches de replication. Des donnees recentes suggerent aussi que la surexpression de KDM4C contribue au maintien d'un etat pluripotent. L'ensemble de ces resultats suggere que la surexpression des proteines KDM4 induit de nombreux effets oncogeniques. [Traduit par la Redaction] Mots-cles: demethylase, H3K9me3, jumonji, JMJD2/KDM4, cancer.
Introduction In the cell, DNA is packaged into chromatin. The basic building block of chromatin is a protein/DNA complex termed the nucleosome, a protein structure composed of 8 histones around [...]