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

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 6; pp. 1494 - 1505
• Main Authors: Raynal, Noël J-M, Lee, Justin T, Wang, Youjun, Beaudry, Annie, Madireddi, Priyanka, Garriga, Judith, Malouf, Gabriel G, Dumont, Sarah, Dettman, Elisha J, Gharibyan, Vazganush, Ahmed, Saira, Chung, Woonbok, Childers, Wayne E, Abou-Gharbia, Magid, Henry, Ryan A, Andrews, Andrew J, Jelinek, Jaroslav, Cui, Ying, Baylin, Stephen B, Gill, Donald L, Issa, Jean-Pierre J
• Format: Journal Article
• Language: English
• Published: United States 15.03.2016
• Subjects: Antineoplastic Agents - pharmacology; Calcium - metabolism; Calcium Signaling - drug effects; Calcium Signaling - genetics; Cell Line; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; CpG Islands - drug effects; CpG Islands - genetics; DNA Methylation - drug effects; DNA Methylation - genetics; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Epigenomics - methods; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene Silencing - drug effects; Genes, Tumor Suppressor - drug effects; HCT116 Cells; HEK293 Cells; Histone Deacetylase Inhibitors - pharmacology; HL-60 Cells; Humans; K562 Cells; Nuclear Proteins - genetics; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Signal Transduction - drug effects; Signal Transduction - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-14-2391

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.