Abstract
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its lack of treatment options. Patients with TNBC frequently develop resistance to chemotherapy. As epigenetic-based antineoplastic drugs, histone deacetylase inhibitors (HDACis) have achieved particular efficacy in lymphoma but are less efficacious in solid tumors, and the resistance mechanism remains poorly understood. In this study, the GSE129944 microarray dataset from the Gene Expression Omnibus database was downloaded, and fold changes at the transcriptome level of a TNBC line (MDA-MB-231) after treatment with belinostat were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the critical biological processes. Construction and analysis of the protein-protein interaction (PPI) network were performed to screen candidate genes related to cancer prognosis. A total of 465 DEGs were identified, including 240 downregulated and 225 upregulated genes. The cytokine-cytokine receptor pathway was identified as being significantly changed. Furthermore, the expression of CXCL1 was implicated as a favorable factor in the overall survival of breast cancer patients. With in vitro approaches, we also showed that belinostat could induce the expression of CXCL1 in another 2 TNBC cell lines (BT-549 and HCC-1937). We speculate that belinostat-induced CXCL1 expression could be one of the results of the stress clone evolution of cells after HDACi treatment. These findings provide new insights into clone evolution during HDACi treatment, which might guide us to a novel perspective that various mutation-targeted treatments should be implemented during the whole treatment cycle.
Highlights
Histone deacetylases (HDACs) catalyze the N-acetyl group’s cleavage from acetylated lysine residues located on the tails of nucleosomal histones
To evaluate the effect of the HDAC inhibitor belinostat on Triple-negative breast cancer (TNBC) cells, the GSE129944 dataset and expression profiles from high-throughput sequencing were collected from the Gene Expression Omnibus (GEO) database
Belinostat treatment led to alterations in the global transcription profile, and 465 differentially expressed genes (DEGs) were obtained from pairwise comparisons of samples, including 240 downregulated and 225 upregulated genes
Summary
Histone deacetylases (HDACs) catalyze the N-acetyl group’s cleavage from acetylated lysine residues located on the tails of nucleosomal histones. By interacting with histone acetyltransferases (HATs), HDACs regulate histone acetylation and influence the expression level of genes. Many nonhistone protein targets, such as transcription factors, transcription regulators, signal transduction mediators, DNA repair enzymes, nuclear import regulators, chaperone proteins, structural proteins, inflammation mediators, and viral proteins, are substrates for HDACs. As a result, HDACs control many oncogenes and apoptotic genes’ expression levels and control many cancer cellular. As the first successful application of epigenetic-based cancer therapy, HDAC inhibitors have been discovered to have specific anticancer activities in preclinical studies and clinical treatments [5]. In 2006, suberoylanilide hydroxamic acid (SAHA, vorinostat) was approved by the US FDA to treat cutaneous T-cell lymphoma (CTCL). Several HDACis have been approved by the FDA for the treatment of other cancers, including peripheral T-cell lymphoma (PTCL) and multiple myeloma [6, 7]. Epigenetic therapy has achieved specific effects in hematologic neoplasia, which has stimulated growing interest and enthusiasm for further developing epigenetic therapies for other malignancies
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