Reynolds Paul A, Sigaroudinia Mahvash, Zardo Giuseppe, Wilson Matthew B, Benton Geoffrey M, Miller Caroline J, Hong Chibo, Fridlyand Jane, Costello Joseph F, Tlsty Thea D
Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143-0511, USA.
J Biol Chem. 2006 Aug 25;281(34):24790-802. doi: 10.1074/jbc.M604175200. Epub 2006 Jun 9.
Alterations in DNA methylation are important in cancer, but the acquisition of these alterations is poorly understood. Using an unbiased global screen for CpG island methylation events, we have identified a non-random pattern of DNA hypermethylation acquired in p16-repressed cells. Interestingly, this pattern included loci located upstream of a number of homeobox genes. Upon removal of p16(INK4A) activity in primary human mammary epithelial cells, polycomb repressors, EZH2 and SUZ12, are up-regulated and recruited to HOXA9, a locus expressed during normal breast development and epigenetically silenced in breast cancer. We demonstrate that at this targeted locus, the up-regulation of polycomb repressors is accompanied by the recruitment of DNA methyltransferases and the hypermethylation of DNA, an endpoint, which we show to be dependent on SUZ12 expression. These results demonstrate a causal role of p16(INK4A) disruption in modulating DNA hypermethylation, and identify a dynamic and active process whereby epigenetic modulation of gene expression is activated as an early event in breast tumor progression.
DNA甲基化改变在癌症中很重要，但这些改变的获得过程却知之甚少。通过对CpG岛甲基化事件进行无偏差的全基因组筛选，我们在p16抑制的细胞中发现了一种非随机的DNA高甲基化模式。有趣的是，这种模式包括一些同源框基因上游的位点。在原代人乳腺上皮细胞中去除p16(INK4A)活性后，多梳抑制因子EZH2和SUZ12上调并被招募到HOXA9，该位点在正常乳腺发育过程中表达，在乳腺癌中表观遗传沉默。我们证明，在这个靶向位点，多梳抑制因子的上调伴随着DNA甲基转移酶的招募和DNA的高甲基化，我们表明这一终点依赖于SUZ12的表达。这些结果证明了p16(INK4A)破坏在调节DNA高甲基化中的因果作用，并确定了一个动态且活跃的过程，即基因表达的表观遗传调节作为乳腺肿瘤进展的早期事件被激活。
