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RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN
Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechan...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737559/ https://www.ncbi.nlm.nih.gov/pubmed/28981843 http://dx.doi.org/10.1093/nar/gkx802 |
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author | Sancisi, Valentina Manzotti, Gloria Gugnoni, Mila Rossi, Teresa Gandolfi, Greta Gobbi, Giulia Torricelli, Federica Catellani, Francesca Faria do Valle, Italo Remondini, Daniel Castellani, Gastone Ragazzi, Moira Piana, Simonetta Ciarrocchi, Alessia |
author_facet | Sancisi, Valentina Manzotti, Gloria Gugnoni, Mila Rossi, Teresa Gandolfi, Greta Gobbi, Giulia Torricelli, Federica Catellani, Francesca Faria do Valle, Italo Remondini, Daniel Castellani, Gastone Ragazzi, Moira Piana, Simonetta Ciarrocchi, Alessia |
author_sort | Sancisi, Valentina |
collection | PubMed |
description | Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene. |
format | Online Article Text |
id | pubmed-5737559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-57375592018-01-09 RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN Sancisi, Valentina Manzotti, Gloria Gugnoni, Mila Rossi, Teresa Gandolfi, Greta Gobbi, Giulia Torricelli, Federica Catellani, Francesca Faria do Valle, Italo Remondini, Daniel Castellani, Gastone Ragazzi, Moira Piana, Simonetta Ciarrocchi, Alessia Nucleic Acids Res Molecular Biology Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene. Oxford University Press 2017-11-02 2017-09-07 /pmc/articles/PMC5737559/ /pubmed/28981843 http://dx.doi.org/10.1093/nar/gkx802 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Molecular Biology Sancisi, Valentina Manzotti, Gloria Gugnoni, Mila Rossi, Teresa Gandolfi, Greta Gobbi, Giulia Torricelli, Federica Catellani, Francesca Faria do Valle, Italo Remondini, Daniel Castellani, Gastone Ragazzi, Moira Piana, Simonetta Ciarrocchi, Alessia RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN |
title | RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN |
title_full | RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN |
title_fullStr | RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN |
title_full_unstemmed | RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN |
title_short | RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN |
title_sort | runx2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of brd4 and c-jun |
topic | Molecular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737559/ https://www.ncbi.nlm.nih.gov/pubmed/28981843 http://dx.doi.org/10.1093/nar/gkx802 |
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