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Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling
Breast cancer metastatic relapse after a latency period, known as metastatic dormancy. Through genetic screening in mice, we identified the mediator complex subunit 4 (Med4) as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation. Med4 downregulation effectively awakened dormant breast...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680920/ https://www.ncbi.nlm.nih.gov/pubmed/38014033 http://dx.doi.org/10.1101/2023.11.18.566087 |
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author | Bae, Seong-Yeon Chen, Yi Chen, Hong Kumar, Dhiraj Karaiskos, Spyros Xu, Jane Lu, Chao Viny, Aaron D. Giancotti, Filippo G. |
author_facet | Bae, Seong-Yeon Chen, Yi Chen, Hong Kumar, Dhiraj Karaiskos, Spyros Xu, Jane Lu, Chao Viny, Aaron D. Giancotti, Filippo G. |
author_sort | Bae, Seong-Yeon |
collection | PubMed |
description | Breast cancer metastatic relapse after a latency period, known as metastatic dormancy. Through genetic screening in mice, we identified the mediator complex subunit 4 (Med4) as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation. Med4 downregulation effectively awakened dormant breast cancer cells, prompting macroscopic metastatic outgrowth in the lungs. Med4 depletion results in profound changes in nuclear size and three-dimensional chromatin architecture from compacted to relaxed states in contrast to the canonical function of the Mediator complex. These changes rewire the expression of extracellular matrix proteins, integrins, and signaling components resulting in integrin-mediated mechano-transduction and activation of YAP and MRTF. The assembly of stress fibers pulls on the nuclear membrane and contributes to reinforcing the overall chromatin modifications by Med4 depletion. MED4 gene deletions were observed in patients with metastatic breast cancer, and reduced MED4 expression correlates with worse prognosis, highlighting its significance as a potential biomarker for recurrence. |
format | Online Article Text |
id | pubmed-10680920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-106809202023-11-27 Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling Bae, Seong-Yeon Chen, Yi Chen, Hong Kumar, Dhiraj Karaiskos, Spyros Xu, Jane Lu, Chao Viny, Aaron D. Giancotti, Filippo G. bioRxiv Article Breast cancer metastatic relapse after a latency period, known as metastatic dormancy. Through genetic screening in mice, we identified the mediator complex subunit 4 (Med4) as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation. Med4 downregulation effectively awakened dormant breast cancer cells, prompting macroscopic metastatic outgrowth in the lungs. Med4 depletion results in profound changes in nuclear size and three-dimensional chromatin architecture from compacted to relaxed states in contrast to the canonical function of the Mediator complex. These changes rewire the expression of extracellular matrix proteins, integrins, and signaling components resulting in integrin-mediated mechano-transduction and activation of YAP and MRTF. The assembly of stress fibers pulls on the nuclear membrane and contributes to reinforcing the overall chromatin modifications by Med4 depletion. MED4 gene deletions were observed in patients with metastatic breast cancer, and reduced MED4 expression correlates with worse prognosis, highlighting its significance as a potential biomarker for recurrence. Cold Spring Harbor Laboratory 2023-11-19 /pmc/articles/PMC10680920/ /pubmed/38014033 http://dx.doi.org/10.1101/2023.11.18.566087 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Bae, Seong-Yeon Chen, Yi Chen, Hong Kumar, Dhiraj Karaiskos, Spyros Xu, Jane Lu, Chao Viny, Aaron D. Giancotti, Filippo G. Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling |
title | Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling |
title_full | Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling |
title_fullStr | Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling |
title_full_unstemmed | Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling |
title_short | Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling |
title_sort | noncanonical activity of med4 as a gatekeeper of metastasis through epigenetic control of integrin signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680920/ https://www.ncbi.nlm.nih.gov/pubmed/38014033 http://dx.doi.org/10.1101/2023.11.18.566087 |
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