Abstract
Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.
Highlights
During carcinogenesis, genetic and epigenetic alterations lead to dysregulated expression of genes associated with cellular pathways that regulate processes such as cell proliferation, cell differentiation, cell death, and cell cycle, among others
DNA methylation (DNAm) is catalyzed by three DNA methyltransferases (DNMTs), which have been identified in mammals: DNMT1, DNMT3A, and DNMT3B
Several studies have shown that modifications in DNAm patterns may support cancer development, invasion, and metastasis
Summary
Genetic and epigenetic alterations lead to dysregulated expression of genes associated with cellular pathways that regulate processes such as cell proliferation, cell differentiation, cell death, and cell cycle, among others. Epigenetic alterations that include DNA methylation (DNAm), histone modifications, aberrant expression of microRNAs (miRNAs), and long non-coding RNA (lncRNA) are common in several types of cancer. These epigenetic changes are hereditary, transient, and reversible and do not cause modification in the DNA sequence [1]. Several studies have found that some of these DNAm alterations may be associated with tumor clinical features such as disease risk, TNM (tumor, node and metastasis)-stage, prognosis, diagnosis, survival, and response to treatment. We discuss several DNAm alterations in genes and some pathways that have been reported to promote tumor resistance to therapeutic agents. More extensive studies should be further developed by considering the targeting specific alterations in DNAm or editing the epigenome by CRISPR-Cas technology
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