KDM4A Lysine Demethylase Induces Site-Specific Copy Gain and Rereplication of Regions Amplified in Tumors
Menée à partir de données issues du projet "The Cancer Genome Atlas", puis sur des lignées cellulaires, cette étude montre que la surexpression d'une lysine déméthylase (KDM4A) favorise un gain du nombre de copies de gènes dans des régions génomiques spécifiques (1q12, 1q21 et Xq13.1) sans instabilité chromosomique globale
Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1³ overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. This begins to establish how copy number changes could originate during tumorigenesis and demonstrates that transient overexpression of specific chromatin modulators could promote these events. "The KDM4A demethylase is amplified and overexpressed in cancer "Overexpression of KDM4A promotes site-specific copy gain and rereplication "KDM4A transiently promotes site-specific copy gain within a cell cycle "Regions coamplified with KDM4A in tumors are generated in transgenic cell lines Increased expression of the KDM4A demethylase leads to site-specific copy gain during tumorigenesis without causing global chromosomal instability, suggesting that overexpression of specific chromatin modulators can promote copy number variation in cancer.