Abstract 440: Dual epigenetic targeting of hepatocellular carcinoma

Abstract Despite advancements in medical treatment, hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. Combination therapies involving multiple targeted agents are increasingly recognized as effective strategies to improve treatment outcomes and overcome the limitations of single-agent therapies. While single-target approaches have shown specificity and potency, they face challenges such as drug resistance, limited pharmacokinetics, and patient adherence. Given the complex nature of HCC, targeting multiple molecular pathways through combination strategies holds promise for more robust therapeutic outcomes. Epigenetic therapies offer a distinct advantage in treating HCC by targeting reversible modifications to reprogram aberrant gene expression and address tumor heterogeneity. These therapies can enhance the efficacy of existing treatments, overcome resistance mechanisms, selectively target cancer cells, and modulate the immune microenvironment, making them a promising avenue for improving HCC outcomes. EZH2 (Enhancer of Zeste Homolog 2) is a histone methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to the silencing of tumor suppressor genes and the promotion of stem cell-like features. LSD1 (Lysine-specific demethylase 1) is a histone demethylase that modulates gene expression to promote tumor progression, cancer stemness, drug resistance, and epithelial-mesenchymal transition (EMT). These epigenetic enzymes form a corepressor complex to inhibit tumor suppressor gene expression. Both EZH2 and LSD1 are overexpressed in HCC and are strongly associated with poor clinical outcomes. Patients with high expression levels of both EZH2 and LSD1 exhibit the poorest survival, suggesting that dual inhibition of these enzymes may offer a more effective therapeutic strategy than monotherapy in HCC. Dual inhibition of EZH2 and LSD1 using GSK126 (an EZH2 inhibitor) and SP2509 (an LSD1 inhibitor) more effectively suppresses liver cancer cell proliferation compared to single-agent treatments. This combination reduces cell proliferation markers, including PCNA and Cyclin D1, and is associated with enhanced programmed cell death. Additionally, we observed decreased cell migration, invasion potential, cancer stem cell characteristics, and drug resistance. Gene Set Enrichment Analysis (GSEA) revealed that high expression of either EZH2 or LSD1 is linked to crucial processes such as cell proliferation, migration, invasion, cancer stemness, and EMT, reinforcing the potential of dual epigenetic targeting. Although EZH2 and LSD1 inhibitors are currently undergoing clinical trials for various cancers, their combination has not yet been explored in HCC. Therefore, evaluating this dual epigenetic therapy for HCC treatment represents a promising direction for future research with immediate translational potential. Citation Format: Kyounghyun Kim, Ponmari Guruvaiya. Dual epigenetic targeting of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 440.