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Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins
The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increas...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454690/ https://www.ncbi.nlm.nih.gov/pubmed/37629054 http://dx.doi.org/10.3390/ijms241612874 |
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author | Maksimova, Varvara Popova, Valeriia Prus, Anzhelika Lylova, Evgeniya Usalka, Olga Sagitova, Guzel Zhidkova, Ekaterina Makus, Julia Trapeznikova, Ekaterina Belitsky, Gennady Yakubovskaya, Marianna Kirsanov, Kirill |
author_facet | Maksimova, Varvara Popova, Valeriia Prus, Anzhelika Lylova, Evgeniya Usalka, Olga Sagitova, Guzel Zhidkova, Ekaterina Makus, Julia Trapeznikova, Ekaterina Belitsky, Gennady Yakubovskaya, Marianna Kirsanov, Kirill |
author_sort | Maksimova, Varvara |
collection | PubMed |
description | The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in epigenetic enzymes, and targeting these epigenetic alterations represents a compelling strategy to reverse cell transcriptome to the normal state, improving chemotherapy response. Curaxin CBL0137 is a new potent anticancer drug that has been shown to activate epigenetically silenced genes. However, its detailed effects on the enzymes of the epigenetic system of transcription regulation have not been studied. Here, we report that CBL0137 inhibits the expression of DNA methyltransferase DNMT3a in HeLa TI cells, both at the level of mRNA and protein, and it decreases the level of integral DNA methylation in Ca Ski cells. For the first time, it is shown that CBL0137 decreases the level of BET family proteins, BRD2, BRD3, and BRD4, the key participants in transcription elongation, followed by the corresponding gene expression enhancement. Furthermore, we demonstrate that CBL0137 does not affect the mechanisms of histone acetylation and methylation. The ability of CBL0137 to suppress DNMT3A and BET family proteins should be taken into consideration when combined chemotherapy is applied. Our data demonstrate the potential of CBL0137 to be used in the therapy of tumors with corresponding aberrant epigenetic profiles. |
format | Online Article Text |
id | pubmed-10454690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104546902023-08-26 Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins Maksimova, Varvara Popova, Valeriia Prus, Anzhelika Lylova, Evgeniya Usalka, Olga Sagitova, Guzel Zhidkova, Ekaterina Makus, Julia Trapeznikova, Ekaterina Belitsky, Gennady Yakubovskaya, Marianna Kirsanov, Kirill Int J Mol Sci Article The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in epigenetic enzymes, and targeting these epigenetic alterations represents a compelling strategy to reverse cell transcriptome to the normal state, improving chemotherapy response. Curaxin CBL0137 is a new potent anticancer drug that has been shown to activate epigenetically silenced genes. However, its detailed effects on the enzymes of the epigenetic system of transcription regulation have not been studied. Here, we report that CBL0137 inhibits the expression of DNA methyltransferase DNMT3a in HeLa TI cells, both at the level of mRNA and protein, and it decreases the level of integral DNA methylation in Ca Ski cells. For the first time, it is shown that CBL0137 decreases the level of BET family proteins, BRD2, BRD3, and BRD4, the key participants in transcription elongation, followed by the corresponding gene expression enhancement. Furthermore, we demonstrate that CBL0137 does not affect the mechanisms of histone acetylation and methylation. The ability of CBL0137 to suppress DNMT3A and BET family proteins should be taken into consideration when combined chemotherapy is applied. Our data demonstrate the potential of CBL0137 to be used in the therapy of tumors with corresponding aberrant epigenetic profiles. MDPI 2023-08-17 /pmc/articles/PMC10454690/ /pubmed/37629054 http://dx.doi.org/10.3390/ijms241612874 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Maksimova, Varvara Popova, Valeriia Prus, Anzhelika Lylova, Evgeniya Usalka, Olga Sagitova, Guzel Zhidkova, Ekaterina Makus, Julia Trapeznikova, Ekaterina Belitsky, Gennady Yakubovskaya, Marianna Kirsanov, Kirill Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins |
title | Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins |
title_full | Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins |
title_fullStr | Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins |
title_full_unstemmed | Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins |
title_short | Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins |
title_sort | insights into the mechanism of curaxin cbl0137 epigenetic activity: the induction of dna demethylation and the suppression of bet family proteins |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454690/ https://www.ncbi.nlm.nih.gov/pubmed/37629054 http://dx.doi.org/10.3390/ijms241612874 |
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