The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent
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Carmen Brenner1, Judith Luciani1, Martin Bizet1, Matladi Ndlovu1, Eleonore Josseaux1, Sarah Dedeurwaerder1, Emilie Calonne1, Pascale Putmans1, Pierre-Francois Cartron2,3,4, Matthieu Defrance1, François Fuks1, Rachel Deplus1
1Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium
2Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, BP7021, 44007 Nantes, France
3Département de Recherche en Cancérologie, Faculté de Médecine, Université de Nantes, IFR26, F-4400, Nantes, France
4LaBCT, Institut de Cancérologie de l’Ouest, 44805 Nantes, Saint Herblain Cedex, France
Rachel Deplus, email: [email protected]
Keywords: DNA methylation, histone demethylation, cancer, KDM1A, cell cycle
Received: January 05, 2016 Accepted: July 06, 2016 Published: July 16, 2016
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.
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