Journal of Clinical & Experimental Pharmacology

The Relationship between DNA Methylation and Drug Resistance in Liver Cancer

David Dadgar^* Department of Biotechnology, College of Science and Technology, Temple University, Philadelphia, USA
^*Correspondence: David Dadgar, Department of Biotechnology, College of Science and Technology, Temple University, Philadelphia, USA, Email:

Received: 06-May-2024, Manuscript No. CPECR-24-26373; Editor assigned: 08-May-2024, Pre QC No. CPECR-24-26373 (PQ); Reviewed: 22-May-2024, QC No. CPECR-24-26373; Revised: 29-May-2024, Manuscript No. CPECR-24-26373 (R); Published: 06-Jun-2024, DOI: 10.35248/2161-1459.24.14.425

Description

Liver cancer, particularly Hepatocellular Carcinoma (HCC), remains a formidable challenge in oncology due to its high prevalence and mortality rates. One of the most significant hurdles in treating liver cancer is the development of drug resistance, which diminishes the efficacy of chemotherapy and targeted therapies. Recent research has increasingly highlighted the role of epigenetic modifications, particularly DNA methylation, in contributing to drug resistance in liver cancer. Understanding this relationship is important for developing new therapeutic strategies and improving patient outcomes.

DNA methylation

DNA methylation is the process of adding a methyl group to the cytosine base within the DNA sequence, mainly occurring at CpG dinucleotides. This epigenetic modification plays a vital role in regulating gene expression, maintaining genomic stability, and modulating cellular differentiation and development. Aberrant DNA methylation patterns, including hypermethylation and hypomethylation, have been implicated in various cancers, including liver cancer. These changes can result in the silencing of tumor suppressor genes or the activation of oncogenes, thereby promoting tumor development and progression.

Mechanisms of drug resistance in liver cancer

Drug resistance in liver cancer can arise through multiple mechanisms, including genetic mutations, alterations in drug transport and metabolism, changes in cell cycle regulation, and epigenetic modifications such as DNA methylation. These mechanisms can act independently or synergistically, making drug resistance a complex and multifaceted phenomenon.

The role of dna methylation in drug resistance:

Gene silencing and activation: DNA methylation can directly influence drug resistance by altering the expression of genes involved in drug response. Hypermethylation of promoter regions in tumor suppressor genes can silence these genes, leading to decreased sensitivity to chemotherapeutic agents. For instance, the hypermethylation of the RASSF1A gene, a known tumor suppressor, has been associated with poor prognosis and resistance to chemotherapeutic drugs in liver cancer patients.

Conversely, hypomethylation can lead to the activation of oncogenes or drug-resistance genes. Hypomethylation of the ABCB1 gene, which encodes the drug efflux pump P- glycoprotein, can result in increased drug efflux and reduced intracellular drug accumulation, thereby contributing to drug resistance.

Epigenetic reprogramming: Cancer cells can undergo epigenetic reprogramming in response to drug treatment, leading to the emergence of drug-resistant cell populations. This reprogramming can involve global changes in DNA methylation patterns, which can alter the expression of multiple genes simultaneously. For example, studies have shown that treatment with chemotherapeutic agents can induce DNA methylation changes that promote the survival and proliferation of drug-resistant liver cancer cells.

Interaction with other epigenetic modifications: DNA methylation does not act in isolation but interacts with other epigenetic modifications such as histone modifications and non- coding RNAs. These interactions can create complex regulatory networks that contribute to drug resistance. For instance, DNA methylation can recruit Methyl-CpG-Binding Domain proteins (MBDs) and Histone Deacetylases (HDACs), leading to chromatin remodeling and transcriptional repression of genes involved in drug sensitivity.

Clinical implications and therapeutic strategies

Understanding the relationship between DNA methylation and drug resistance in liver cancer has significant clinical implications. It opens up new methods for the development of diagnostic and therapeutic strategies aimed at overcoming drug resistance.

Biomarkers for predicting drug response: DNA methylation patterns can serve as biomarkers for predicting response to therapy and patient prognosis. For example, the methylation status of specific genes such as RASSF1A and ABCB1 can be used to identify patients who are likely to respond poorly to conventional chemotherapy. This information can guide personalized treatment strategies and help in selecting alternative therapeutic approaches for non-responders.

Epigenetic therapy: Targeting DNA methylation with epigenetic drugs, such as DNA Methyltransferase inhibitors (DNMTis), hold the potential for overcoming drug resistance. Agents like 5- azacytidine and decitabine can reverse abnormal DNA methylation patterns, thereby restoring the expression of silenced tumor suppressor genes and sensitizing cancer cells to chemotherapy. Combining DNMTis with conventional chemotherapeutic agents or targeted therapies may enhance treatment efficacy and overcome resistance in liver cancer.

Combination therapies: The complexity of drug resistance necessitates combination therapies that target multiple pathways simultaneously. Combining epigenetic therapies with other treatments, such as immunotherapy or targeted therapy, may provide synergistic effects and improve clinical outcomes. For instance, combining DNMTis with immune checkpoint inhibitors can enhance the anti-tumor immune response and overcome immune evasion mechanisms in drug-resistant liver cancer.

The relationship between DNA methylation and drug resistance in liver cancer is complex and multifaceted. By modulating gene expression and interacting with other epigenetic modifications, DNA methylation plays an important role in the development of drug resistance. Understanding these mechanisms offers valuable insights into the biology of liver cancer and provides a foundation for developing novel therapeutic strategies. Continued research in this field is essential to translate these findings into clinical practice and improve the prognosis for liver cancer patients facing drug resistance.