Demethylation and Re-Expression of Epigenetically Silenced Tumor Suppressor Genes: Sensitization of Cancer Cells by Combination Therapy

Abstract

Epigenetic regulation in eukaryotic and mammalian systems is a complex and emerging field of study. While histone modifications create an open chromatin conformation allowing for gene transcription, CpG methylation adds a further dimension to the expression of specific genes in developmental pathways and carcinogenesis. In this review, we will highlight DNA methylation as one of the distinct mechanisms for gene silencing and try to provide insight into the role of epigenetics in cancer progenitor cell formation and carcinogenesis. We will also introduce the concept of a dynamic methylation–demethylation system and the potential for the existence of a demethylating enzyme in this process. Finally, we will explain how re-expression of epigenetically silenced tumor suppressor genes could be exploited to develop effective drug therapies. In particular, we will consider how a combination therapy that includes epigenetic drugs could possibly kill cancer progenitor cells and reduce the chance of relapse following chemotherapy.

KEYWORDS::

• cancer
• cancer progenitor cells
• combination therapy
• demethylating agents
• demethylation
• epigenetics
• HDAC inhibitors
• imprinting
• methylation
• tumor suppressor gene

Financial & competing interests disclosure

The work of S Sarkar was supported by a grant from American Cancer Society. S Goldgar and S Byler were supported by the MSSRP, Boston University School of Medicine (MA, USA). S Rosenthal and S Heerboth were supported by UROP, Boston University (MA, USA). 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.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The work of S Sarkar was supported by a grant from American Cancer Society. S Goldgar and S Byler were supported by the MSSRP, Boston University School of Medicine (MA, USA). S Rosenthal and S Heerboth were supported by UROP, Boston University (MA, USA). 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. No writing assistance was utilized in the production of this manuscript.