Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A

Background: There is increasing interest in the role of epigenetic mechanisms in the diagnosis, prognosis, and treatment of breast cancer (BC) within the context of precision oncology. This study aimed to evaluate the clinical significance of euchromatic histone lysine methyltransferase 2 (EHMT2), histone deacetylase 1 (HDAC1), and HDAC2 in BC, assess the antitumor efficacy of combining the selective inhibitors UNC0638 and CI-994 (U+C), and explore the underlying mechanisms.

Methods: Multi-omic analysis was employed to assess the clinical relevance of the targeted biomarkers. The effects of U+C treatment were evaluated through cell viability, cell cycle analysis, apoptosis detection, and expression of key genes. RNA-Seq and Gene Set Enrichment Analysis (GSEA) were used to identify genes significantly associated with the treatment. Chromatin immunoprecipitation and qPCR (ChIP-qPCR) assays were utilized to verify epigenetic changes at specific gene promoters.

Results: Elevated expression levels of EHMT2, HDAC1, and HDAC2 in tumor tissues, particularly in the basal-like subtype of BC, were associated with poor prognosis. The U+C combination treatment exhibited stronger tumor-suppressive effects compared to single-agent treatments. It disrupted the cell cycle, induced apoptosis, and downregulated genes linked to anti-apoptotic processes, stemness, drug resistance, and the basal-like state, while enhancing the expression of genes associated with the luminal-like state. Additionally, combined U+C treatment inhibited xenograft tumor growth. Epigenetic reprogramming was observed, with a downregulation of BIRC5 and an upregulation of GADD45A.

Conclusion: These results indicate that selective targeting of EHMT2, HDAC1, and HDAC2 with the combined U+C treatment suppresses BC tumor progression through epigenetic remodeling of BIRC5 and GADD45A.