Modulating epigenetic modifications for cancer therapy (Review)

Abstract

Cancer is a global public health concern. Alterations in epigenetic processes are among the earliest genomic aberrations occurring during cancer development and are closely related to progression. Unlike genetic mutations, aberrations in epigenetic processes are reversible, which opens the possibility for novel pharmacological treatments. Non‑coding RNAs (ncRNAs) represent an essential epigenetic mechanism, and emerging evidence links ncRNAs to carcinogenesis. Epigenetic drugs (epidrugs) are a group of promising target therapies for cancer treatment acting as coadjuvants to reverse drug resistance in cancer. The present review describes central epigenetic aberrations during malignant transformation and explains how epidrugs target DNA methylation, histone modifications and ncRNAs. Furthermore, clinical trials focused on evaluating the effect of these epidrugs alone or in combination with other anticancer therapies and other ncRNA‑based therapies are discussed. The use of epidrugs promises to be an effective tool for reversing drug resistance in some patients with cancer.

Keywords: cancer; epigenetic drugs; epigenetic mechanisms; non‑coding RNA; therapy.

Figure 1.

Six epigenetic mechanisms involved in the regulation of gene expression. (1) Nuclear dynamics: The structural and three-dimensional organization of the genome in the nucleus, and short- and long-range interconnected transcriptional regulation, which impacts gene expression. (2) DNA methylation: The addition of a methyl group to cytosine nucleotides by DNA methyltransferases, which induces transcriptional repression. (3) Covalent histone modification: The addition of chemical groups to the amino terminus of histones, which can increase or decrease DNA compaction. (4) ATP-dependent chromatin remodeling complexes: Insertion, removal and displacement of nucleosomes along the DNA through ATP hydrolysis to regulate DNA accessibility. (5) Histone variants: Histone chaperones exchange canonical histones for histone variants (H2A.Z, H2A.X, H3.3 and CENP-A). (6) Non-coding RNA: Non-coding RNA expression promotes transcriptional silencing. Overall, this enables chromatin structure modification to regulate gene expression. Ac, acetyl group; lncRNA, long non-coding RNA; Me, methyl group; miRNA, microRNA.

Figure 2.

Epigenetic alterations and their contribution to carcinogenesis. (A) Loss or gain of different histone modifications can induce aberrant gene expression and promote carcinogenesis in different tumors. The gain of H3K4me3 by HMT and the loss of H3K9ac by HDAC contributes to the expression of genes associated with carcinogenesis. (B) Alterations in the pattern of DNA methylation and the expression of enzymes, such as DNMTs, are found in several tumors. DNA hypomethylation in various regions increases genomic instability and activates proto-oncogenes, whereas DNA hypermethylation favors the silencing of genes, such as tumor suppressors, which contributes to carcinogenesis. (C) Changes in non-coding RNA expression patterns serve an important role in regulating the initiation and progression of various tumors because they can inhibit or increase gene expression through binding to various target genes. Ac, acetylation; DNMT, DNA methyltransferase; H, histone; HDAC, histone deacetylase; K, lysine; HMT, histone methyltransferase; lncRNA, long non-coding RNA; me1, monomethylation; me3, trimethylation; miRNA, microRNA; Pol II, RNA polymerase II; SAM, S-adenosyl methionine; TF, transcription factor.

Figure 3.

Inhibitor epigenetic modifications and action in cancer. (A) DNA methylation is catalyzed by DNMTs and involves the addition of a methyl group to cytosine, producing 5-methylcytosine. DNMTi, such as 5-aza-C and 5-aza-D, prevent DNA methylation and restore the function of aberrantly silenced genes in cancer. Therapeutic approaches targeting non-coding RNAs in cancer may be directed to one of two aims: (B) Restoring tumor suppressor activity through mimicking molecules (TargomiRs and MRX34) and synthetic RNAs (MTL-CEBPA) or (C) inhibiting oncogene expression through the employment of molecules that promote the degradation of target mRNAs (MRG-106 and Dovitinib). (D) Histone tails in the nucleosome can be post-translationally modified by the covalent attachment of acetyl groups. Histone deacetylation catalyzed by HDAC modifies the histone code. Various HDACi have been approved by the US Food and Drug Administration for their use as antineoplastic drugs, including vorinostat, romidepsin, belinostat and panobinostat. 5-aza-C, 5-azacytidine; 5-aza-D, 5-aza-2′-deoxycytidine; Ac, acetyl group; DNMT, DNA methyltransferase; DNMTi, DNMT inhibitors; HDAC, histone deacetylase; HDACi, HDAC inhibitors; Me, methyl group; MTL-CEBPA, RNA duplex acting of c/ebpa gen transcription; CEBPA, CCAAT/enhancer-binding protein alpha; MRX34, mimic of miR-34a.

Figure 4.

Chemical structures of DNA demethylating agents (cytidine analogs 5-aza-C and 5-aza-D) approved by the United States Food and Drug Administration as antineoplastic drugs. 5-aza-C, 5-azacytidine; 5-aza-D, 5-aza-2′-deoxycytidine.