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

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). We performed an epigenetic drug screen using FDA-approved libraries to identify agents that reactivate silenced gene expression in colon cancer cells. In this manner, we identified 3 known epigenetic drugs (DNA methylation and histone deacetylase inhibitors) plus 11 other drugs that were sufficient to reactivate a GFP reporter gene under the control of methylated and silenced CpG island promoters. Notably, these agents also induced the expression of endogenous TSG known to be silenced in multiple cancer cell lines. The newly identified drugs, most prominently cardiac glycosides, did not alter DNA methylation locally or histone modifications globally. Instead, all 11 drugs modulated 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, demonstrating that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Collectively, our findings identify calcium signaling as a new pathway that can be targeted to reactivate TSG in cancer.