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Specific inhibition of one DNMT1-including complex influences tumor initiation and progression
BACKGROUND: Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation-induced oncogene activation and chromosomal instability. To...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727981/ https://www.ncbi.nlm.nih.gov/pubmed/23809695 http://dx.doi.org/10.1186/1868-7083-5-9 |
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author | Cheray, Mathilde Pacaud, Romain Nadaradjane, Arulraj Vallette, François M Cartron, Pierre-François |
author_facet | Cheray, Mathilde Pacaud, Romain Nadaradjane, Arulraj Vallette, François M Cartron, Pierre-François |
author_sort | Cheray, Mathilde |
collection | PubMed |
description | BACKGROUND: Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation-induced oncogene activation and chromosomal instability. To develop more specific DNMT inhibitors for efficient cancer therapy, we compared the effects of peptides designed to specifically disrupt the interaction of DNMT1 with different proteins. FINDINGS: Our data indicated that the use of an unspecific DNMT inhibitor (5aza-2deoxycytidine), a DNMT1 inhibitor (procainamide) or peptides disrupting the DNMT1/PCNA, DNMT1/EZH2, DNMT1/HDAC1, DNMT1/DNMT3b and DNMT1/HP1 interactions promoted or enhanced in vivo tumorigenesis in a mouse glioma model. In contrast, a peptide disrupting the DNMT1/DMAP1 interaction, which per se did not affect tumor growth, sensitized cancer cells to chemotherapy/irradiation-induced cell death. Finally, our data indicated that the peptide disrupting the DNMT1/DMAP1 interaction increased the efficiency of temozolomide treatment. CONCLUSION: Our data suggest that the DNMT1/DMAP1 interaction could be an effective anti-cancer target and opens a new avenue for the development of new strategies to design DNMT inhibitors. |
format | Online Article Text |
id | pubmed-3727981 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-37279812013-07-31 Specific inhibition of one DNMT1-including complex influences tumor initiation and progression Cheray, Mathilde Pacaud, Romain Nadaradjane, Arulraj Vallette, François M Cartron, Pierre-François Clin Epigenetics Short Report BACKGROUND: Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation-induced oncogene activation and chromosomal instability. To develop more specific DNMT inhibitors for efficient cancer therapy, we compared the effects of peptides designed to specifically disrupt the interaction of DNMT1 with different proteins. FINDINGS: Our data indicated that the use of an unspecific DNMT inhibitor (5aza-2deoxycytidine), a DNMT1 inhibitor (procainamide) or peptides disrupting the DNMT1/PCNA, DNMT1/EZH2, DNMT1/HDAC1, DNMT1/DNMT3b and DNMT1/HP1 interactions promoted or enhanced in vivo tumorigenesis in a mouse glioma model. In contrast, a peptide disrupting the DNMT1/DMAP1 interaction, which per se did not affect tumor growth, sensitized cancer cells to chemotherapy/irradiation-induced cell death. Finally, our data indicated that the peptide disrupting the DNMT1/DMAP1 interaction increased the efficiency of temozolomide treatment. CONCLUSION: Our data suggest that the DNMT1/DMAP1 interaction could be an effective anti-cancer target and opens a new avenue for the development of new strategies to design DNMT inhibitors. BioMed Central 2013-06-28 /pmc/articles/PMC3727981/ /pubmed/23809695 http://dx.doi.org/10.1186/1868-7083-5-9 Text en Copyright © 2013 Cheray et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Short Report Cheray, Mathilde Pacaud, Romain Nadaradjane, Arulraj Vallette, François M Cartron, Pierre-François Specific inhibition of one DNMT1-including complex influences tumor initiation and progression |
title | Specific inhibition of one DNMT1-including complex influences tumor initiation and progression |
title_full | Specific inhibition of one DNMT1-including complex influences tumor initiation and progression |
title_fullStr | Specific inhibition of one DNMT1-including complex influences tumor initiation and progression |
title_full_unstemmed | Specific inhibition of one DNMT1-including complex influences tumor initiation and progression |
title_short | Specific inhibition of one DNMT1-including complex influences tumor initiation and progression |
title_sort | specific inhibition of one dnmt1-including complex influences tumor initiation and progression |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727981/ https://www.ncbi.nlm.nih.gov/pubmed/23809695 http://dx.doi.org/10.1186/1868-7083-5-9 |
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