KDM4A Promotes Site-Specific Copy Number Gain

Recurring amplifications of specific genomic loci are observed in human cancers, but the factors that predispose to copy number gains are poorly understood. Given previous findings showing that focal amplification events occur during S phase and that lysine (K)-specific demethylase 4A (KDM4A), an H3K9/36me3 demethylase, regulates DNA accessibility and replication timing, Black and colleagues hypothesized that KDM4A could provide a link between local chromatin structure and copy number variation. Analysis of KDM4A copy number and expression level in The Cancer Genome Atlas revealed that amplification and overexpression of KDM4A occurred in 18.9% of tumors overall and in 46% of ovarian cancers. Stable overexpression of KDM4A did not induce large-scale genomic instability but instead resulted in a specific increase in KDM4A occupancy at chromosome 1q12 and focal amplification of this locus in 14% of cells. Gain of 1q12 was specifically dependent on KDM4A, required KDM4A enzymatic activity, and could be suppressed by overexpression of the H3K9me3 methyltransferase SUV39H1 or the H3K9me3-binding protein heterochromatin protein 1γ (HP1γ). Interestingly, 1q12 copy gain was not stably inherited but was generated during S phase of each cell cycle before being eliminated by the end of G2. KDM4A directly bound and recruited the MCM complex and DNA polymerase to 1q12 and induced rereplication of this locus in association with decreased H3K9me3 and HP1γ occupancy, suggesting that KDM4A can induce site-specific copy number gain by altering local chromatin structure and recruiting the DNA replication machinery. In primary tumors, KDM4A amplification was not only correlated with gain of 1q12 but was also correlated with gain of 1q21 and Xq13.1, which were likewise found to be rereplicated in KDM4A-overexpressing cells. Although the reason why these particular loci are amplified upon KDM4A overexpression remains unclear, these findings establish that deregulation of a chromatin modulator can result in site-specific copy number abnormalities.

Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J, et al. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 2013;154:541–55.

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