Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation
Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased t...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609907/ https://www.ncbi.nlm.nih.gov/pubmed/28968975 http://dx.doi.org/10.18632/oncotarget.18668 |
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author | Huang, Yin-Cheng Lin, Sheng-Jia Shih, Hung-Yu Chou, Chung-Han Chu, Hsiao-Han Chiu, Ching-Chi Yuh, Chiou-Hwa Yeh, Tu-Hsueh Cheng, Yi-Chuan |
author_facet | Huang, Yin-Cheng Lin, Sheng-Jia Shih, Hung-Yu Chou, Chung-Han Chu, Hsiao-Han Chiu, Ching-Chi Yuh, Chiou-Hwa Yeh, Tu-Hsueh Cheng, Yi-Chuan |
author_sort | Huang, Yin-Cheng |
collection | PubMed |
description | Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3. NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors. |
format | Online Article Text |
id | pubmed-5609907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56099072017-09-29 Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation Huang, Yin-Cheng Lin, Sheng-Jia Shih, Hung-Yu Chou, Chung-Han Chu, Hsiao-Han Chiu, Ching-Chi Yuh, Chiou-Hwa Yeh, Tu-Hsueh Cheng, Yi-Chuan Oncotarget Research Paper Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3. NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors. Impact Journals LLC 2017-06-27 /pmc/articles/PMC5609907/ /pubmed/28968975 http://dx.doi.org/10.18632/oncotarget.18668 Text en Copyright: © 2017 Huang et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Huang, Yin-Cheng Lin, Sheng-Jia Shih, Hung-Yu Chou, Chung-Han Chu, Hsiao-Han Chiu, Ching-Chi Yuh, Chiou-Hwa Yeh, Tu-Hsueh Cheng, Yi-Chuan Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation |
title | Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation |
title_full | Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation |
title_fullStr | Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation |
title_full_unstemmed | Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation |
title_short | Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation |
title_sort | epigenetic regulation of notch1 and notch3 by kmt2a inhibits glioma proliferation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609907/ https://www.ncbi.nlm.nih.gov/pubmed/28968975 http://dx.doi.org/10.18632/oncotarget.18668 |
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