Multiple exogenous or endogenous factors alter gene expression patterns by different mechanisms that are poorly understood. We used RNA-Seq analysis in order to study changes in gene expression in melanoma cells that are capable of vasculogenic mimicry that is inhibited upon the action of an inhibitor of vasculogenic mimicry. Here, we show that the drug induces a strong upregulation of 50 genes that control the cell cycle and microtubule cytoskeleton coupled with a strong downregulation of 50 genes that control different cellular metabolic processes. We found that both groups of genes are simultaneously regulated by multiple sets of transcription factors. We conclude that one way for coordinated regulation of large groups of genes is regulation simultaneously by multiple transcription factors.

Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including the iris, the ciliary body, and the choroid. UM accounts for 5% of all melanoma cases and is extremely aggressive with half of the UM patients developing metastases within the first 1-2 years after tumor development. Molecular mechanisms of UM carcinogenesis are poorly understood, but are known to differ from those of skin melanoma. Activating mutations of the GNAQ and GNA11 genes, which code for the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The Gaq/PKC/MAPK signaling pathway is a main signaling cascade that leads to the transformation of melanocytes of the uveal tract, and major regulators of the cascade provide targets for the development of drugs. Metastatic UM (MUM) is most often associated with mutations of BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, is highly efficient in predicting the risk of metastasis. The risk of metastasis determines the choice of therapy and the patient follow-up regimen. However, no systemic therapy for MUM has been developed to date. New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

The main molecular mechanisms of the protective effect of minor bioactive compounds (BAC) of food, including rutin and hesperidin, along with antiradical and antioxidant activity, include their interaction with transcription factors modulating the functional state of the organism defense systems, one of which is the system of xenobiotic metabolizing enzymes. However, the data on their combined action are limited. The aim of the research was to study the effect of rutin and hesperidin on the activity and gene expression of cytochrome P450 isoforms 1A and 3A (CYP1A1, CYP1A2, CYP3A) in rat liver at their separate and combined intake. Material and methods. The study was carried out using 4 groups of 6 male Wistar rats with initial body weight 225±5 g. For 14 days the rats of the control group received a standard semi-synthetic diet. Rutin and hesperidin were administered separately or together at a calculated daily dose of 400 mg per 1 kg body weight. CYP1A1 and CYP1A2 activities were determined spectrofluorimetrically in liver microsomal fraction, CYP3A activity - by high-performance liquid chromatography. Gene expression was analyzed by real-time reverse transcription polymerase chain reaction. Results. Dietary intake of rutin and hesperidin did not significantly alter the activity of the studied enzymes of xenobiotic metabolism, but had an inducing effect on CYP1A1 and CYP1A2 genes, expression of which statistically significant increased both at separate and combined intake. The expression of CYP3A1 gene did not differ from control values at intake of rutin alone, but considerably and statistically significant decreased in the presence of hesperidin in the diet. An increase in transcription factor AhR gene expression was noted, moreover the expression in the group receiving rutin + hesperidin was significantly reduced in relation to the group receiving rutin alone. Conclusion. Combined intake of flavonoids (rutin and hesperidin) has a modulating effect on enzymes of xenobiotic metabolism at the level of their gene expression.