Epigenetic modulators for brain cancer stem cells: Implications for anticancer treatment

Abstract

Primary malignant brain tumors are a major cause of morbidity and mortality in both adults and children, with a dismal prognosis despite multimodal therapeutic approaches. In the last years, a specific subpopulation of cells within the tumor bulk, named cancer stem cells (CSCs) or tumor-initiating cells, have been identified in brain tumors as responsible for cancer growth and disease progression. Stemness features of tumor cells strongly affect treatment response, leading to the escape from conventional therapeutic approaches and subsequently causing tumor relapse. Recent research efforts have focused at identifying new therapeutic strategies capable of specifically targeting CSCs in cancers by taking into consideration their complex nature. Aberrant epigenetic machinery plays a key role in the genesis and progression of brain tumors as well as inducing CSC reprogramming and preserving CSC characteristics. Thus, reverting the cancer epigenome can be considered a promising therapeutic strategy. Three main epigenetic mechanisms have been described: DNA methylation, histone modifications, and non-coding RNA, particularly microRNAs. Each of these mechanisms has been proven to be targetable by chemical compounds, known as epigenetic-based drugs or epidrugs, that specifically target epigenetic marks. We review here recent advances in the study of epigenetic modulators promoting and sustaining brain tumor stem-like cells. We focus on their potential role in cancer therapy.

Keywords: Brain tumors; Cancer stem cells; DNA methyltransferase inhibitors; Epigenetic drugs; Epigenetics; Histone deacetylase inhibitors.

Figure 1

Epigenetic mechanism in cancer stem cells and therapeutical approaches. Epigenetic modifiers: Non-coding RNA, DNA methylation, and histone modifications. Non-coding RNAs (microRNAs) regulate gene expression. microRNA expression can be regulated by other epigenetic modifiers. DNA methyltransferases add a methyl group to cytosine in the DNA sequence. This results in aberrant gene silencing and changes in normal gene expression. Posttranslational modifications of histone proteins (acetylation in purple and methylation in red) can affect chromatin structure. Histone enzymes add/remove acetyl or methyl groups. Histone deacetylases and DNMTs are the main targets of epigenetic inhibitors. CSC: Cancer stem cell; Me: Methyl group; Ac: Acetyl group; DNMT: DNA methyltransferases; HDAC: Histone deacetylases; HAT: Histone acetyltransferases; HMT: Histone methyltransferases; HDM: Histone demethylases; DNMTi: DNA methyltransferases inhibitors; HDACi: Histone deacetylases inhibitors.