The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent.
The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent.
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DOI：
10.18632/oncotarget.10624
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Deplus R
中科院分区：
文献类型：
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作者：
Brenner C;Luciani J;Bizet M;Ndlovu M;Josseaux E;Dedeurwaerder S;Calonne E;Putmans P;Cartron PF;Defrance M;Fuks F;Deplus R
DNA甲基化和组蛋白修饰是基因表达的关键表观遗传调节因素，两者之间存在密切联系。DNA甲基转移酶在几种肿瘤中上调，DNA甲基化异常是癌症的标志。另一方面，组蛋白去甲基酶在癌细胞中表达上调。先前对ES细胞的研究表明，赖氨酸去甲基酶KDM1a与DNMT1结合，从而影响DNA甲基化。在癌细胞中，这种相互作用的发生还没有被探索过。在这里，我们在几个肿瘤细胞系中演示了KDM1a与DNMT1和DNMT3b之间的相互作用。有趣的是，与在ES细胞中观察到的情况相反，癌细胞中的KDM1a缺失被发现不会引发DNMT1或Dnmt3b蛋白水平的任何降低或DNA甲基化的任何变化。在S期，KDM1a和DNMT1共定位于异染色质内。利用P-LISA，我们发现KDM1a与DNMT1的结合在S阶段显著增加。总之，我们的发现提出了癌细胞中KDM1A和DNA甲基转移酶之间的机制联系，并表明KDM1A/DNMT1相互作用可能在复制过程中发挥作用。我们的工作也加强了DNMT可以发挥与DNA甲基化无关的功能的想法。
DNA methylation and histone modifications are key epigenetic regulators of gene expression, and tight connections are known between the two. DNA methyltransferases are upregulated in several tumors and aberrant DNA methylation profiles are a cancer hallmark. On the other hand, histone demethylases are upregulated in cancer cells. Previous work on ES cells has shown that the lysine demethylase KDM1A binds to DNMT1, thereby affecting DNA methylation. In cancer cells, the occurrence of this interaction has not been explored. Here we demonstrate in several tumor cell lines an interaction between KDM1A and both DNMT1 and DNMT3B. Intriguingly and in contrast to what is observed in ES cells, KDM1A depletion in cancer cells was found not to trigger any reduction in the DNMT1 or DNMT3B protein level or any change in DNA methylation. In the S-phase, furthermore, KDM1A and DNMT1 were found, to co-localize within the heterochromatin. Using P-LISA, we revealed substantially increased binding of KDM1A to DNMT1 during the S-phase. Together, our findings propose a mechanistic link between KDM1A and DNA methyltransferases in cancer cells and suggest that the KDM1A/DNMT1 interaction may play a role during replication. Our work also strengthens the idea that DNMTs can exert functions unrelated to act on DNA methylation.