Abstract
G-quadruplexes (G4) are secondary nucleic acid structures that have been associated with genomic instability and cancer progression. When present in the promoter of some oncogenes, G4 structures can affect gene regulation and, hence, represent a possible therapeutic target. In this study, RNA-Seq was used to explore the effect of a G4-binding anthraquinone derivative, named AQ1, on the whole-transcriptome profiles of two common cell models for the study of KIT pathways; the human mast cell leukemia (HMC1.2) and the canine mast cell tumor (C2). The highest non-cytotoxic dose of AQ1 (2 µM) resulted in 5441 and 1201 differentially expressed genes in the HMC1.2 and C2 cells, respectively. In both cell lines, major pathways such as cell cycle progression, KIT- and MYC-related pathways were negatively enriched in the AQ1-treated group, while other pathways such as p53, apoptosis and hypoxia-related were positively enriched. These findings suggest that AQ1 treatment induces a similar functional response in the human and canine cell models, and provide news insights into using dogs as a reliable translational model for studying G4-binding compounds.
Highlights
In the past decade, several studies have been focusing on guanine-rich stretches found in important genomic regions such as telomeres, centromeres, immunoglobulin switch regions, mutational hot spots, and promoter elements[14]
Studies have shown that several proto-oncogenes like v-myc avian myelocytomatosis viral oncogene homolog (MYC), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), B-cell lymphoma 2 (BCL2), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and hypoxia-inducible factor (HIF) bear G4 motifs in their promoters[16,18,19,20,21,22,23,24]
Two KIT G4-forming sequences (d_kit[1] and d_kit2) were discovered in the canine genome (Supplementary Fig. S1)[32]. They showed a high degree of homology with the corresponding human sequences, and preliminary studies were conducted to assess their interaction with AQ133
Summary
Several studies have been focusing on guanine-rich stretches found in important genomic regions such as telomeres, centromeres, immunoglobulin switch regions, mutational hot spots, and promoter elements[14]. In the present study, we investigated - using RNA-Seq- the AQ1-induced effects on the global gene expression in two species-specific KIT-dependent cancer cell lines, in order to identify which cellular pathways are likely to be affected by treatment. For this purpose, we used the HMC1.2 human mast cell leukemia and the C2 canine mast cell tumor cell line, which are two common models for the study of tyrosine kinase inhibitors and, in particular, the proto-oncogene KIT
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