Abstract
The development of resistance to anti-cancer therapeutics remains one of the core issues preventing the improvement of survival rates in cancer. Therapy resistance can arise in a multitude of ways, including the accumulation of epigenetic alterations in cancer cells. By remodeling DNA methylation patterns or modifying histone proteins during oncogenesis, cancer cells reorient their epigenomic landscapes in order to aggressively resist anti-cancer therapy. To combat these chemoresistant effects, epigenetic modifiers such as DNA hypomethylating agents, histone deacetylase inhibitors, histone demethylase inhibitors, along with others have been used. While these modifiers have achieved moderate success when used either alone or in combination with one another, the most positive outcomes were achieved when they were used in conjunction with conventional anti-cancer therapies. Epigenome modifying drugs have succeeded in sensitizing cancer cells to anti-cancer therapy via a variety of mechanisms: disrupting pro-survival/anti-apoptotic signaling, restoring cell cycle control and preventing DNA damage repair, suppressing immune system evasion, regulating altered metabolism, disengaging pro-survival microenvironmental interactions and increasing protein expression for targeted therapies. In this review, we explore different mechanisms by which epigenetic modifiers induce sensitivity to anti-cancer therapies and encourage the further identification of the specific genes involved with sensitization to facilitate development of clinical trials.
Highlights
Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology
Efforts to revert these epigenetic changes via the use of epigenome modifying drugs have achieved some success, when used in conjunction with other therapies. While these modifiers are “non-specific” in that they affect gene expression on a global level, their action elicits “specific” effects in malignant cells. This is due to the altered epigenome that is acquired during oncogenesis, highlighted by expression changes in tumor suppressor genes and oncogenes that are responsible for cancer progression or therapy resistance
While there has been strong evidence of the role played by epigenetic-induced metabolic changes in cancer cells in promoting therapy resistance, the study of how epigenetic modifiers can mitigate these effects has yet to be explored in depth
Summary
The term “epigenetics” refers to the study of heritable phenotypic changes that do not involve mutations in DNA sequence [1]. These changes are centered around alterations in gene activity and expression; through a variety of processes including DNA methylation and histone modifications [2]. Methylation in gene bodies affects transcription; demethylation of gene bodies results in a decrease in gene transcription [6]. These patterns of DNA methylation are retained during cell division and can persist across generations
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