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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
Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer
Cancer Res. 2016 Mar 15;76(6) :1494-505
PMID: 26719529    PMCID: PMC4794357    URL: http://www.ncbi.nlm.nih.gov/pubmed/26719529
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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. Cancer Res; 76(6); 1494-505. (c)2015 AACR.
Raynal, Noel 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 eng P01 CA049639/CA/NCI NIH HHS/ P50 CA100632/CA/NCI NIH HHS/ R01 CA158112/CA/NCI NIH HHS/ R01 GM109279/GM/NIGMS NIH HHS/ 2016/01/01 06:00 Cancer Res. 2016 Mar 15;76(6):1494-505. doi: 10.1158/0008-5472.CAN-14-2391. Epub 2015 Dec 30.