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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
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.
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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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