Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.
Fiche publication
Date publication
mars 2016
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MALOUF Gabriel
Tous les auteurs :
Raynal NJ, Lee JT, Wang Y, Beaudry A, Madireddi P, Garriga J, Malouf GG, Dumont S, Dettman EJ, Gharibyan V, Ahmed S, Chung W, Childers WE, Abou-Gharbia M, Henry RA, Andrews AJ, Jelinek J, Cui Y, Baylin SB, Gill DL, Issa JP
Lien Pubmed
Résumé
Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer.
Mots clés
Antineoplastic Agents, pharmacology, Calcium, metabolism, Calcium Signaling, drug effects, Cell Line, Cell Line, Tumor, Colonic Neoplasms, drug therapy, CpG Islands, drug effects, DNA Methylation, drug effects, Epigenesis, Genetic, drug effects, Epigenomics, methods, Gene Expression Regulation, Neoplastic, drug effects, Gene Silencing, drug effects, Genes, Tumor Suppressor, drug effects, HCT116 Cells, HEK293 Cells, HL-60 Cells, Histone Deacetylase Inhibitors, pharmacology, Humans, K562 Cells, Nuclear Proteins, genetics, Promoter Regions, Genetic, drug effects, Signal Transduction, drug effects
Référence
Cancer Res.. 2016 Mar 15;76(6):1494-505