Disable oncogenes
Antitumor molecule disrupted the three-dimensional organization of the genome of cancer cells
Daria Spasskaya, N+1
Russian scientists have discovered an unusual mechanism of action of a new family of antitumor drugs. As stated in an article in Nature Communications (Kantidze et al., The anti-cancer drugs curaxins target spatial genome organization), substances called curaxins disrupt the three-dimensional organization of the genome in cancer cells, which leads to a decrease in the expression of oncogenes and other genes important for cell life.
In the human genome, DNA is organized into structural domains with the help of protein complexes, which facilitate the activation of gene transcription and their interaction with remote regulatory elements – enhancers. Such a three–dimensional organization, in particular, is important for the activation of oncogenes - genes whose excessive function leads to malignant transformation of the cell. Suppression of oncogen activation underlies the mechanism of action of some anticancer drugs.
Relatively recently discovered curaxins, related to the antimalarial drug hinakrin, work, among other things, by suppressing the remote interaction of enhancers with oncogenes, scientists from Institute of Gene Biology of the Russian Academy of Sciences, MSU Biofac and Institute of Bioorganic Chemistry of the Russian Academy of Sciences under the leadership of Sergey Razin. The work was carried out in collaboration with the American cancer research centers Fox Chase and Roswell Park with the support of the Russian Science Foundation, the Russian Foundation for Basic Research, the American National Cancer Institute, the company "Inkuron" and a number of other organizations.
As an object of research, the authors chose a group of oncogenes of the MYC family, the expression of which is most sensitive to the action of kuraxins. On two cancer cell lines, scientists have shown that MYC activation depends on remote enhancers, and on an in vitro model, that kuraxin CBL0137 disrupts the interaction of the enhancer with the promoter ("switch" of transcription) of the gene.
Global study of the structure of chromatin (DNA-protein complex of the nucleus) in the presence of kuraxin, CBL0137 revealed a violation of the general three-dimensional structure of the genome and a change in the boundaries of transcriptionally active domains. The observed violation of oncogen activation apparently occurs due to a global rearrangement of contacts between chromatin sites, which leads to the destruction of the gene-enhancer interaction.
Change in the density of contacts between chromatin sites under the action of CBL0137 (below). A drawing from an article in Nature Communications.
In addition, the rearrangement of the genome led to a decrease in the expression of one and a half thousand genes, a quarter of which are necessary for the vital activity of the cell. This fact also explains the toxicity of kuraxin to cancer cells.
In previous studies, scientists have shown that kuraxins disrupt the interaction of DNA with nucleosomes and interfere with the work of the FACT transcription complex in cancer cells. However, a new mechanism, not previously described for antitumor drugs, affects the change in the physical properties of chromatin – apparently, kuraxin makes DNA protein strands more rigid, including by removing the CTCF protein, and prevents them from bending and forming contacts.
A class of antitumor drugs called kuraxins has been developed and is being investigated with the participation of a Russian company Incuron and the American Cleveland Biolabs, Inc. Currently, the most promising molecule from this group, substance number CBL0137, has successfully passed preclinical tests, and in 2019, regular studies of its effectiveness in patients with melanoma should begin.
Portal "Eternal youth" http://vechnayamolodost.ru