INTERNATIONAL CONGRESS OF
PharmacoGenetics
The Role of Epigenetics and Signaling Pathways in Liver Cancer: A Review of Mechanisms and Therapeutic Applications
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Fatemeh Abolmashadi,1,*
1. PhD student in Pharmaceutical Chemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Tehran, Iran
- Introduction: Liver cancer (particularly hepatocellular carcinoma, HCC) is among the most lethal malignancies of the digestive system. Recent studies have indicated that, in addition to genetic mutations, epigenetic alterations play a crucial role in the onset, progression, and metastasis of HCC. These changes lead to the regulation of gene expression without altering the DNA sequence and include DNA methylation, histone modifications, and regulation by non-coding RNAs (such as miRNAs). The aim of this study is to investigate the role of these mechanisms in the pathogenesis of HCC and their emerging therapeutic applications.
- Methods: This study was conducted as a systematic review, comprehensively examining articles published up to the year 2025 in databases such as PubMed and Google Scholar. The primary focus was on three main aspects of epigenetic changes (DNA methylation, histone modifications, and miRNA) in relation to the pathogenesis, diagnosis, and treatment of HCC.
- Results: Epigenetic alterations play a central role in the pathogenesis of hepatocellular carcinoma (HCC). DNA methylation, particularly the hypermethylation of tumor suppressor gene promoters such as p16, RASSF1A, and CASP8, leads to the silencing of these genes and facilitates the progression of HCC. These changes have also been observed in precancerous stages such as cirrhosis. Conversely, DNA hypomethylation is associated with genomic instability and the activation of oncogenes, with significant reductions in methylation reported in HCC samples. In the realm of histone modifications, histone methylation (for instance, by the enzyme SMYD3) and histone acetylation (by HATs/HDACs) regulate chromatin structure and gene expression. The increased expression of HDAC1, through the induction of epithelial-mesenchymal transition (EMT), and SIRT1, by inhibiting cellular aging, enhances tumor invasion and apoptotic resistance in HCC. Inhibitors of these enzymes, such as SAHA (an HDAC inhibitor) and DZNep (an HMT inhibitor), have been shown to suppress tumor growth in both in vitro and in vivo models. On the other hand, the regulation of miRNA in HCC, through the upregulation of miR-181b and miR-221, leads to the inhibition of tumor suppressor genes (such as TIMP3) and the development of drug resistance. Although shRNA-based therapeutic approaches are promising, studies indicate that even low doses of these molecules can induce liver damage and accelerate tumorigenesis by disrupting the expression of natural miRNA.
- Conclusion: A deeper understanding of epigenetic processes in liver cancer is crucial not only for early diagnosis but also for the development of effective targeted therapies. Given the reversible nature of these changes, the design of drugs that specifically target certain epigenetic pathways opens new horizons for liver cancer treatment. However, due to the complexity of the mechanisms and interactions involved, further research is necessary to identify precise therapeutic targets.
- Keywords: Liver Cancer, Epigenetics, Targeted therapy
