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Cancer Res. 2016 Mar 15;76(6):1494-505. doi: 10.1158/0008-5472.CAN-14-2391. Epub 2015 Dec 30.

Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.

Author information

1
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.
2
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
3
Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University, Beijing, P.R. China.
4
Département de pharmacologie, Université de Montréal and Sainte-Justine University Hospital Research Center, Montréal, Québec, Canada.
5
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania.
7
Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
8
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
9
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania.
10
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania. jpissa@temple.edu.

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.

PMID:
26719529
PMCID:
PMC4794357
DOI:
10.1158/0008-5472.CAN-14-2391
[Indexed for MEDLINE]
Free PMC Article

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