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The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling
Gaining pharmacologic access to the potential of ARID1A, a tumor suppressor protein, to mediate transcriptional control over cancer gene expression is an unresolved challenge. Retinoid X receptor ligands are pleiotropic, incompletely understood tools that regulate breast epithelial cell proliferatio...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381091/ https://www.ncbi.nlm.nih.gov/pubmed/35320351 http://dx.doi.org/10.1158/1541-7786.MCR-21-0961 |
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author | Jdeed, Sham Erdős, Edina Bálint, Bálint L. Uray, Iván P. |
author_facet | Jdeed, Sham Erdős, Edina Bálint, Bálint L. Uray, Iván P. |
author_sort | Jdeed, Sham |
collection | PubMed |
description | Gaining pharmacologic access to the potential of ARID1A, a tumor suppressor protein, to mediate transcriptional control over cancer gene expression is an unresolved challenge. Retinoid X receptor ligands are pleiotropic, incompletely understood tools that regulate breast epithelial cell proliferation and differentiation. We found that low-dose bexarotene (Bex) combined with the nonselective beta-blocker carvedilol (Carv) reduces proliferation of MCF10DCIS.com cells and markedly suppresses ARID1A levels. Similarly, Carv synergized with Bex in MCF-7 cells to suppress cell growth. Chromatin immunoprecipitation sequencing analysis revealed that under nonestrogenic conditions Bex + Carv alters the concerted genomic distribution of the chromatin remodeler ARID1A and acetylated histone H3K27, at sites related to insulin-like growth factor (IGF) signaling. Several distinct sites of ARID1A enrichment were identified in the IGF-1 receptor and IRS1 genes, associated with a suppression of both proteins. The knock-down of ARID1A increased IGF-1R levels, prevented IGF-1R and IRS1 suppression upon Bex + Carv, and stimulated proliferation. In vitro IGF-1 receptor neutralizing antibody suppressed cell growth, while elevated IGF-1R or IRS1 expression was associated with poor survival of patients with ER-negative breast cancer. Our study demonstrates direct impact of ARID1A redistribution on the expression and growth regulation of IGF-1–related genes, induced by repurposed clinical drugs under nonestrogenic conditions. IMPLICATIONS: This study underscores the possibility of the pharmacologic modulation of the ARID1A factor to downregulate protumorigenic IGF-1 activity in patients with postmenopausal breast cancer undergoing aromatase inhibitor treatment. |
format | Online Article Text |
id | pubmed-9381091 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93810912023-01-05 The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling Jdeed, Sham Erdős, Edina Bálint, Bálint L. Uray, Iván P. Mol Cancer Res Cancer “-Omics” Gaining pharmacologic access to the potential of ARID1A, a tumor suppressor protein, to mediate transcriptional control over cancer gene expression is an unresolved challenge. Retinoid X receptor ligands are pleiotropic, incompletely understood tools that regulate breast epithelial cell proliferation and differentiation. We found that low-dose bexarotene (Bex) combined with the nonselective beta-blocker carvedilol (Carv) reduces proliferation of MCF10DCIS.com cells and markedly suppresses ARID1A levels. Similarly, Carv synergized with Bex in MCF-7 cells to suppress cell growth. Chromatin immunoprecipitation sequencing analysis revealed that under nonestrogenic conditions Bex + Carv alters the concerted genomic distribution of the chromatin remodeler ARID1A and acetylated histone H3K27, at sites related to insulin-like growth factor (IGF) signaling. Several distinct sites of ARID1A enrichment were identified in the IGF-1 receptor and IRS1 genes, associated with a suppression of both proteins. The knock-down of ARID1A increased IGF-1R levels, prevented IGF-1R and IRS1 suppression upon Bex + Carv, and stimulated proliferation. In vitro IGF-1 receptor neutralizing antibody suppressed cell growth, while elevated IGF-1R or IRS1 expression was associated with poor survival of patients with ER-negative breast cancer. Our study demonstrates direct impact of ARID1A redistribution on the expression and growth regulation of IGF-1–related genes, induced by repurposed clinical drugs under nonestrogenic conditions. IMPLICATIONS: This study underscores the possibility of the pharmacologic modulation of the ARID1A factor to downregulate protumorigenic IGF-1 activity in patients with postmenopausal breast cancer undergoing aromatase inhibitor treatment. American Association for Cancer Research 2022-07-06 2022-03-23 /pmc/articles/PMC9381091/ /pubmed/35320351 http://dx.doi.org/10.1158/1541-7786.MCR-21-0961 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Cancer “-Omics” Jdeed, Sham Erdős, Edina Bálint, Bálint L. Uray, Iván P. The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling |
title | The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling |
title_full | The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling |
title_fullStr | The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling |
title_full_unstemmed | The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling |
title_short | The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling |
title_sort | role of arid1a in the nonestrogenic modulation of igf-1 signaling |
topic | Cancer “-Omics” |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381091/ https://www.ncbi.nlm.nih.gov/pubmed/35320351 http://dx.doi.org/10.1158/1541-7786.MCR-21-0961 |
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