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Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance
Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357761/ https://www.ncbi.nlm.nih.gov/pubmed/27694900 http://dx.doi.org/10.1038/onc.2016.320 |
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author | Ramadoss, S Sen, S Ramachandran, I Roy, S Chaudhuri, G Farias-Eisner, R |
author_facet | Ramadoss, S Sen, S Ramachandran, I Roy, S Chaudhuri, G Farias-Eisner, R |
author_sort | Ramadoss, S |
collection | PubMed |
description | Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21(Waf1/Cip1). The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21(Waf1/Cip1) expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer. |
format | Online Article Text |
id | pubmed-5357761 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53577612017-03-30 Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance Ramadoss, S Sen, S Ramachandran, I Roy, S Chaudhuri, G Farias-Eisner, R Oncogene Original Article Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21(Waf1/Cip1). The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21(Waf1/Cip1) expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer. Nature Publishing Group 2017-03 2016-10-03 /pmc/articles/PMC5357761/ /pubmed/27694900 http://dx.doi.org/10.1038/onc.2016.320 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Ramadoss, S Sen, S Ramachandran, I Roy, S Chaudhuri, G Farias-Eisner, R Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance |
title | Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance |
title_full | Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance |
title_fullStr | Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance |
title_full_unstemmed | Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance |
title_short | Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance |
title_sort | lysine-specific demethylase kdm3a regulates ovarian cancer stemness and chemoresistance |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357761/ https://www.ncbi.nlm.nih.gov/pubmed/27694900 http://dx.doi.org/10.1038/onc.2016.320 |
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