title: The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent.
abstract: 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.
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Judith
authors.initials: J
authors.lastname: Luciani
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Martin
authors.initials: M
authors.lastname: Bizet
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Matladi
authors.initials: M
authors.lastname: Ndlovu
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Josseaux
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dedeurwaerder
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Calonne
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Putmans
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et progression tumorale, BP7021, 44007 Nantes, France.|Département de Recherche en Cancérologie, Faculté de Médecine, Université de Nantes, IFR26, F-4400, Nantes, France.|LaBCT, Institut de Cancérologie de l'Ouest,44805 Nantes, Saint Herblain Cedex, France.
authors.forename: Pierre-Francois
authors.initials: PF
authors.lastname: Cartron
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Defrance
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Fuks
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Rachel
authors.initials: R
authors.lastname: Deplus
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D059807:S Phase Cell Cycle Checkpoints; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D056466:Histone Demethylases; D006657:Histones; D008239:Lysine; D000097584:DNA Methyltransferase 3B; C495195:KDM1A protein, human; C000619380:DNMT1 protein, human
keywords: DNA methylation; KDM1A; cancer; cell cycle; histone demethylation