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The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells
The chromodomain helicase DNA-binding 4 (CHD4), a member of the nucleosome remodeling and deacetylases (NuRD) complex, has been identified as an oncogene that modulates proliferation and migration of breast cancers (BC). ERBB2 is an oncogenic driver in 20–30% of BC in which its overexpression leads...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The Company of Biologists Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504000/ https://www.ncbi.nlm.nih.gov/pubmed/30967373 http://dx.doi.org/10.1242/bio.038323 |
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author | D'Alesio, Carolina Bellese, Grazia Gagliani, Maria Cristina Lechiara, Anastasia Dameri, Martina Grasselli, Elena Lanfrancone, Luisa Cortese, Katia Castagnola, Patrizio |
author_facet | D'Alesio, Carolina Bellese, Grazia Gagliani, Maria Cristina Lechiara, Anastasia Dameri, Martina Grasselli, Elena Lanfrancone, Luisa Cortese, Katia Castagnola, Patrizio |
author_sort | D'Alesio, Carolina |
collection | PubMed |
description | The chromodomain helicase DNA-binding 4 (CHD4), a member of the nucleosome remodeling and deacetylases (NuRD) complex, has been identified as an oncogene that modulates proliferation and migration of breast cancers (BC). ERBB2 is an oncogenic driver in 20–30% of BC in which its overexpression leads to increased chemoresistance. Here we investigated whether CHD4 depletion affects the ERBB2 cascade and autophagy, which represents a mechanism of resistance against Trastuzumab (Tz), a therapeutic anti-ERBB2 antibody. We show that CHD4 depletion in two ERBB2(+) BC cell lines strongly inhibits cell proliferation, induces p27(KIP1) upregulation, Tyr(1248) ERBB2 phosphorylation, ERK1/2 and AKT dephosphorylation, and downregulation of both ERBB2 and PI3K levels. Moreover, CHD4 silencing impairs late stages of autophagy, resulting in increased levels of LC3 II and SQSTM1/p62, lysosomal enlargement and accumulation of autolysosomes (ALs). Importantly, we show that CHD4 depletion and concomitant treatment with Tz prevent cell proliferation in vitro. Our results suggest that CHD4 plays a critical role in modulating cell proliferation, ERBB2 signaling cascade and autophagy and provide new insights on CHD4 as a potential target for the treatment of ERBB2(+) BC. |
format | Online Article Text |
id | pubmed-6504000 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-65040002019-05-08 The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells D'Alesio, Carolina Bellese, Grazia Gagliani, Maria Cristina Lechiara, Anastasia Dameri, Martina Grasselli, Elena Lanfrancone, Luisa Cortese, Katia Castagnola, Patrizio Biol Open Research Article The chromodomain helicase DNA-binding 4 (CHD4), a member of the nucleosome remodeling and deacetylases (NuRD) complex, has been identified as an oncogene that modulates proliferation and migration of breast cancers (BC). ERBB2 is an oncogenic driver in 20–30% of BC in which its overexpression leads to increased chemoresistance. Here we investigated whether CHD4 depletion affects the ERBB2 cascade and autophagy, which represents a mechanism of resistance against Trastuzumab (Tz), a therapeutic anti-ERBB2 antibody. We show that CHD4 depletion in two ERBB2(+) BC cell lines strongly inhibits cell proliferation, induces p27(KIP1) upregulation, Tyr(1248) ERBB2 phosphorylation, ERK1/2 and AKT dephosphorylation, and downregulation of both ERBB2 and PI3K levels. Moreover, CHD4 silencing impairs late stages of autophagy, resulting in increased levels of LC3 II and SQSTM1/p62, lysosomal enlargement and accumulation of autolysosomes (ALs). Importantly, we show that CHD4 depletion and concomitant treatment with Tz prevent cell proliferation in vitro. Our results suggest that CHD4 plays a critical role in modulating cell proliferation, ERBB2 signaling cascade and autophagy and provide new insights on CHD4 as a potential target for the treatment of ERBB2(+) BC. The Company of Biologists Ltd 2019-04-09 /pmc/articles/PMC6504000/ /pubmed/30967373 http://dx.doi.org/10.1242/bio.038323 Text en © 2019. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article D'Alesio, Carolina Bellese, Grazia Gagliani, Maria Cristina Lechiara, Anastasia Dameri, Martina Grasselli, Elena Lanfrancone, Luisa Cortese, Katia Castagnola, Patrizio The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells |
title | The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells |
title_full | The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells |
title_fullStr | The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells |
title_full_unstemmed | The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells |
title_short | The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells |
title_sort | chromodomain helicase chd4 regulates erbb2 signaling pathway and autophagy in erbb2(+) breast cancer cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504000/ https://www.ncbi.nlm.nih.gov/pubmed/30967373 http://dx.doi.org/10.1242/bio.038323 |
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