title: Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.
abstract: 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.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania. Département de pharmacologie, Université de Montréal and Sainte-Justine University Hospital Research Center, Montréal, Québec, Canada.
authors.forename: Noël J-M
authors.initials: NJ
authors.lastname: Raynal
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University, Beijing, P.R. China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Département de pharmacologie, Université de Montréal and Sainte-Justine University Hospital Research Center, Montréal, Québec, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Beaudry
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Madireddi
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Judith
authors.initials: J
authors.lastname: Garriga
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dumont
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elisha J
authors.initials: EJ
authors.lastname: Dettman
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vazganush
authors.initials: V
authors.lastname: Gharibyan
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Saira
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Woonbok
authors.initials: W
authors.lastname: Chung
authors.affiliation: Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania.
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
authors.affiliation: Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania.
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Henry
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andrews
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gill
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania. jpissa@temple.edu.
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D057890:Epigenomics / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D045325:HCT116 Cells; D057809:HEK293 Cells; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D002118:Calcium