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

• Published in: Biomedicine & pharmacotherapy 2022-01, Vol.145, p.112431-112431, Article 112431
• Main Authors: Lin, Hung-Yu, Wu, Hsing-Ju, Chen, Si-Yun, Hou, Ming-Feng, Lin, Chang-Shen, Chu, Pei-Yi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Benzamides - administration & dosage; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Cycle Proteins - genetics; Cell Line, Tumor; CI-994 (tacedinaline); combination therapy; Disease Progression; Epigenesis, Genetic; epigenetic therapy; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; Phenylenediamines - administration & dosage; Quinazolines - administration & dosage; Survivin - genetics; UNC0638; Xenograft Model Antitumor Assays
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112431

There is currently a growing interest in the roles of epigenetic mechanisms in the diagnosis, prognosis, and therapies associated with precision oncology for breast cancer (BC). This study aimed to demonstrate the clinical significance of euchromatic histone lysine methyltransferase 2 (EHMT2), histone deacetylase 1 (HDAC1) and HDAC2 in BC, to evaluate the antitumor effectiveness of a combination of the selective inhibitors UNC0638 and CI-994 (U+C), and to clarify the underlying mechanisms. Multi-omic analysis was used to study the clinical significance of the biomarkers of interest. The effects of U+C treatment were evaluated by detecting cell viability, cell cycle, apoptosis, and representative gene expressions. RNA-Seq and Gene Set Enrichment Analysis (GSEA) were employed to identify over-represented genes associated with the treatment. Chromatin immunoprecipitation and qPCR (ChIP-qPCR) assay were applied to verify epigenetic profiling on the identified promoters. The significance of elevated expressions of EHMT2, HDAC1, and HDAC2 in tumor tissue and BC basal-like subtype in predicting a poor prognosis was noted. The U+C combined treatment showed an enhanced suppressive effect as compared to single agent treatment, perturbed the cell cycle, induced apoptosis, reduced expressions of the genes representing anti-apoptosis, stemness, drug resistance and basal-like state, while increasing luminal-like state genes. In addition, the combined U+C treatment suppressed xenograft tumor growth. The epigenetic reprogramming of histones was identified in the down-regulated BIRC5 and upregulated GADD45A. These findings demonstrate that selectively targeting EHMT2, HDAC1, and HDAC2 by concurrent U+C treatment suppresses BC tumor progression via epigenetic remodeling of BIRC5 and GADD45A. [Display omitted] •EHMT2, HDAC1 and HDAC2 presents diagnosis and prognosis value in BC patients.•Targeting EHMT2, HDAC1, and HDAC2 by the combined UNC0638 and CI-994 suppresses BC tumor growth.•Combined UNC0638 and CI-994 reduces BC stemness and basal-like subtype state.•Epigenetic reprogramming of BIRC5 and GADD45A is implicated in the BC suppression.