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A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma
Temozolomide (TMZ) was used for the treatment of glioblastoma (GBM) for over a decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that an enhancer, located between the promoters of marker of proliferation Ki67 (MKI67)...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063898/ https://www.ncbi.nlm.nih.gov/pubmed/30054476 http://dx.doi.org/10.1038/s41467-018-05373-4 |
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author | Chen, Xiaoyue Zhang, Minjie Gan, Haiyun Wang, Heping Lee, Jeong-Heon Fang, Dong Kitange, Gaspar J. He, Lihong Hu, Zeng Parney, Ian F. Meyer, Fredric B. Giannini, Caterina Sarkaria, Jann N. Zhang, Zhiguo |
author_facet | Chen, Xiaoyue Zhang, Minjie Gan, Haiyun Wang, Heping Lee, Jeong-Heon Fang, Dong Kitange, Gaspar J. He, Lihong Hu, Zeng Parney, Ian F. Meyer, Fredric B. Giannini, Caterina Sarkaria, Jann N. Zhang, Zhiguo |
author_sort | Chen, Xiaoyue |
collection | PubMed |
description | Temozolomide (TMZ) was used for the treatment of glioblastoma (GBM) for over a decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that an enhancer, located between the promoters of marker of proliferation Ki67 (MKI67) and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines and recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to a dramatic reduction of MGMT and a lesser extent of Ki67 expression, increased TMZ sensitivity, and impaired proliferation. Together, these studies uncover a mechanism that regulates MGMT expression, confers TMZ resistance, and potentially regulates tumor proliferation. |
format | Online Article Text |
id | pubmed-6063898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60638982018-07-30 A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma Chen, Xiaoyue Zhang, Minjie Gan, Haiyun Wang, Heping Lee, Jeong-Heon Fang, Dong Kitange, Gaspar J. He, Lihong Hu, Zeng Parney, Ian F. Meyer, Fredric B. Giannini, Caterina Sarkaria, Jann N. Zhang, Zhiguo Nat Commun Article Temozolomide (TMZ) was used for the treatment of glioblastoma (GBM) for over a decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that an enhancer, located between the promoters of marker of proliferation Ki67 (MKI67) and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines and recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to a dramatic reduction of MGMT and a lesser extent of Ki67 expression, increased TMZ sensitivity, and impaired proliferation. Together, these studies uncover a mechanism that regulates MGMT expression, confers TMZ resistance, and potentially regulates tumor proliferation. Nature Publishing Group UK 2018-07-27 /pmc/articles/PMC6063898/ /pubmed/30054476 http://dx.doi.org/10.1038/s41467-018-05373-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Chen, Xiaoyue Zhang, Minjie Gan, Haiyun Wang, Heping Lee, Jeong-Heon Fang, Dong Kitange, Gaspar J. He, Lihong Hu, Zeng Parney, Ian F. Meyer, Fredric B. Giannini, Caterina Sarkaria, Jann N. Zhang, Zhiguo A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma |
title | A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma |
title_full | A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma |
title_fullStr | A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma |
title_full_unstemmed | A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma |
title_short | A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma |
title_sort | novel enhancer regulates mgmt expression and promotes temozolomide resistance in glioblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063898/ https://www.ncbi.nlm.nih.gov/pubmed/30054476 http://dx.doi.org/10.1038/s41467-018-05373-4 |
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