Targeting of cancer stem cells by inhibitors of DNA and histone methylation

Abstract

Introduction: Curative chemotherapy should target cancer stem cells (CSCs). The key characteristics of CSCs are a block in differentiation and an epigenetic signature similar to embryonic stem cells (ESCs). Differentiation by ESCs and CSCs is suppressed by gene silencing through the polycomb repressive complex 2 (PRC2) and/or DNA methylation. PRC2 contains the EZH2 subunit, which catalyzes the trimethylation of histone 3 lysine 27, a gene silencing marker. It is possible to reverse this ‘double lock’ mechanism using a combination of inhibitors of EZH2 and DNA methylation (5-aza-2’-deoxycytidine), which exhibits remarkable synergistic antineoplastic activity in preclinical studies.

Areas covered: The authors discuss several specific EZH2 inhibitors that have been synthesized with antineoplastic activity. One such inhibitor, EPZ-6438 (E7438), has been shown to be effective against lymphoma in a Phase I study. The indirect EZH2 inhibitor, 3-deazaneplanocin-A (DZNep), also exhibits remarkable anticancer activity due to its inhibition of methionine metabolism.

Expert opinion: Agents that target EZH2 warrant Phase I trials. Due to its positive pharmacodynamics, DZNep merits a high priority for clinical investigation. Agents that show positive results in Phase I studies should be advanced to clinical trials for use in combination with 5-aza-2’-deoxycytidine due to the interesting potential of this epigenetic therapy to target CSCs.

Keywords:

• 3-deazaneplanocin-A
• 5-aza-2’-deoxycytidine
• cancer stem cells
• decitabine
• embryonic stem cells
• epigenetic therapy
• EPZ-6438 (E7438)
• EZH2 inhibitors
• GSK-126
• histone methyltransferase
• polycomb repressive complex 2

Acknowledgments

We thank V Marquez for valuable discussion on DZNep and G Chabot for the inspiration to write this review. The authors are also grateful to NPG language editing for their help in improving the accuracy and clarity of the language.

Declaration of interest

The authors are supported by the Canadian Cancer Society Research Institute grant number. 700795. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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