Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer

Noël J.M. Raynal, Justin T. Lee, Youjun Wang, Annie Beaudry, Priyanka Madireddi, Judith Garriga, Gabriel G. Malouf, Sarah Dumont, Elisha J. Dettman, Vazganush Gharibyan, Saira Ahmed, Woonbok Chung, Wayne E. Childers, Magid Abou-Gharbia, Ryan A. Henry, Andrew J. Andrews, Jaroslav Jelinek, Ying Cui, Stephen B. Baylin, Donald L. GillJean Pierre J. Issa

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1494-1505
Number of pages12
JournalCancer Research
Volume76
Issue number6
DOIs
StatePublished - Mar 15 2016

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Calcium Signaling
Tumor Suppressor Genes
Epigenomics
Pharmaceutical Preparations
Neoplasms
Calcium-Calmodulin-Dependent Protein Kinases
DNA Methylation
Histone Code
Calcium
Cardiac Glycosides
CpG Islands
Histone Deacetylase Inhibitors
Neoplasm Genes
Reporter Genes
Colonic Neoplasms
Gene Expression
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Raynal, N. J. M., Lee, J. T., Wang, Y., Beaudry, A., Madireddi, P., Garriga, J., ... Issa, J. P. J. (2016). Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. Cancer Research, 76(6), 1494-1505. https://doi.org/10.1158/0008-5472.CAN-14-2391
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. / Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. In: Cancer Research. 2016 ; Vol. 76, No. 6. pp. 1494-1505.
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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.",
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Raynal, NJM, 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, JPJ 2016, 'Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer', Cancer Research, vol. 76, no. 6, pp. 1494-1505. https://doi.org/10.1158/0008-5472.CAN-14-2391

Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. / 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.

In: Cancer Research, Vol. 76, No. 6, 15.03.2016, p. 1494-1505.

Research output: Contribution to journalArticle

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AU - Raynal, Noël J.M.

AU - Lee, Justin T.

AU - Wang, Youjun

AU - Beaudry, Annie

AU - Madireddi, Priyanka

AU - Garriga, Judith

AU - Malouf, Gabriel G.

AU - Dumont, Sarah

AU - Dettman, Elisha J.

AU - Gharibyan, Vazganush

AU - Ahmed, Saira

AU - Chung, Woonbok

AU - Childers, Wayne E.

AU - Abou-Gharbia, Magid

AU - Henry, Ryan A.

AU - Andrews, Andrew J.

AU - Jelinek, Jaroslav

AU - Cui, Ying

AU - Baylin, Stephen B.

AU - Gill, Donald L.

AU - Issa, Jean Pierre J.

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N2 - 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.

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