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Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc
Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814060/ https://www.ncbi.nlm.nih.gov/pubmed/33462212 http://dx.doi.org/10.1038/s41419-020-03380-2 |
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author | Lee, Dong Hoon Kim, Go Woon Yoo, Jung Lee, Sang Wu Jeon, Yu Hyun Kim, So Yeon Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee Choi, Junjeong Kwon, So Hee |
author_facet | Lee, Dong Hoon Kim, Go Woon Yoo, Jung Lee, Sang Wu Jeon, Yu Hyun Kim, So Yeon Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee Choi, Junjeong Kwon, So Hee |
author_sort | Lee, Dong Hoon |
collection | PubMed |
description | Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM4C’s roles in glioblastoma and the underlying molecular mechanisms remain unclear. Here, we show that KDM4C knockdown significantly represses proliferation and tumorigenesis of glioblastoma cells in vitro and in vivo that are rescued by overexpressing wild-type KDM4C but not a catalytic dead mutant. KDM4C protein expression is upregulated in glioblastoma, and its expression correlates with c-Myc expression. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. Importantly, KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53K372me1, which is pivotal for the stability of chromatin-bound p53. Conversely, depletion or inhibition of KDM4C promotes p53 target gene expression and induces apoptosis in glioblastoma. KDM4C may serve as an oncogene through the dual functions of inactivation of p53 and activation of c-Myc in glioblastoma. Our study demonstrates KDM4C inhibition as a promising therapeutic strategy for targeting glioblastoma. |
format | Online Article Text |
id | pubmed-7814060 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78140602021-01-25 Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc Lee, Dong Hoon Kim, Go Woon Yoo, Jung Lee, Sang Wu Jeon, Yu Hyun Kim, So Yeon Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee Choi, Junjeong Kwon, So Hee Cell Death Dis Article Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM4C’s roles in glioblastoma and the underlying molecular mechanisms remain unclear. Here, we show that KDM4C knockdown significantly represses proliferation and tumorigenesis of glioblastoma cells in vitro and in vivo that are rescued by overexpressing wild-type KDM4C but not a catalytic dead mutant. KDM4C protein expression is upregulated in glioblastoma, and its expression correlates with c-Myc expression. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. Importantly, KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53K372me1, which is pivotal for the stability of chromatin-bound p53. Conversely, depletion or inhibition of KDM4C promotes p53 target gene expression and induces apoptosis in glioblastoma. KDM4C may serve as an oncogene through the dual functions of inactivation of p53 and activation of c-Myc in glioblastoma. Our study demonstrates KDM4C inhibition as a promising therapeutic strategy for targeting glioblastoma. Nature Publishing Group UK 2021-01-18 /pmc/articles/PMC7814060/ /pubmed/33462212 http://dx.doi.org/10.1038/s41419-020-03380-2 Text en © The Author(s) 2021 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 Lee, Dong Hoon Kim, Go Woon Yoo, Jung Lee, Sang Wu Jeon, Yu Hyun Kim, So Yeon Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee Choi, Junjeong Kwon, So Hee Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
title | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
title_full | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
title_fullStr | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
title_full_unstemmed | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
title_short | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
title_sort | histone demethylase kdm4c controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-myc |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814060/ https://www.ncbi.nlm.nih.gov/pubmed/33462212 http://dx.doi.org/10.1038/s41419-020-03380-2 |
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