Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.
Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.
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DOI：
10.1158/0008-5472.can-14-2391
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Issa JP
中科院分区：
文献类型：
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作者：
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
靶向表观遗传途径是一种很有前途的癌症治疗方法。在这里，我们报告了一个意想不到的发现，即靶向钙信号可以逆转肿瘤抑制基因（TSGs）的表观遗传沉默。在结肠癌细胞中重新激活沉默基因表达的药物筛选中，我们发现了三种经典的表观遗传靶向药物（DNA甲基化和组蛋白去乙酰化酶抑制剂）和11种在多种癌细胞系中诱导甲基化和沉默CpG岛启动子驱动报告基因（GFP）以及内源性TSGs的药物。这些新发现的药物，最突出的是心脏糖苷，不会改变局部DNA甲基化或全局组蛋白修饰。相反，所有11种药物都改变钙信号并触发钙钙调蛋白激酶（CamK）活性，导致MeCP2核排斥。阻断CamK活性可消除这些药物的基因再激活和癌细胞杀伤，表明触发钙通量是其表观遗传作用机制的重要组成部分。我们的数据确定钙信号是一种新的途径，可以靶向重新激活癌症中的tsg。
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 (TSGs). 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 induce 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.