<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer

The role of <i>SMARCA4</i>, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investig...

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Autores principales:	Jihyun Kim, Gyubeom Jang, Sung Hoon Sim, In Hae Park, Kyungtae Kim, Charny Park
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	triple-negative breast cancer cisplatin resistance molecular subtype <i>SMARCA4</i> epithelial-to-mesenchymal Hippo-YAP/TAZ pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/098fe13511404653a3dec055bf5a64a8
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spelling	oai:doaj.org-article:098fe13511404653a3dec055bf5a64a82021-11-11T15:33:36Z<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer10.3390/cancers132154742072-6694https://doaj.org/article/098fe13511404653a3dec055bf5a64a82021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5474https://doaj.org/toc/2072-6694The role of <i>SMARCA4</i>, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investigated the clinical implication and downstream regulation induced by <i>SMARCA4</i> inactivation using large-scale genome and transcriptome profiles. Additionally, <i>SMARCA4</i> was knocked out in MDA-MB-468 and MDA-MB-231 using CRISPR/Cas9 to identify gene regulation and a targetable pathway. First, we observed an increase in <i>SMARCA4</i> mutations in cisplatin resistance and metastasis in TNBC patients. Its inactivation was associated with the mesenchymal-like (MSL) subtype. Gene expression analysis showed that the epithelial-to-mesenchymal transition (EMT) pathway was activated in <i>SMARCA4</i>-deficient patients. Next, the Hippo pathway was activated in the <i>SMARCA4</i> inactivation group, as evidenced by the higher <i>CTNNB1</i>, <i>TGF-β</i>, and <i>YAP1</i> oncogene signature scores. In <i>SMARCA4</i> knockout cells, EMT was upregulated, and the cell line transcriptome changed from the SL to the MSL subtype. <i>SMARCA4</i> knockout cells showed cisplatin resistance and Hippo-YAP/TAZ target gene activation. The YAP1 inhibitor verteporfin suppressed the expression of <i>YAP1</i> target genes, and decreased cell viability and invasiveness on <i>SMARCA4</i> knockout cells. <i>SMARCA4</i> inactivation in TNBC endowed the resistance to cisplatin via EMT activation. The YAP1 inhibitor could become a novel strategy for patients with <i>SMARCA4</i>-inactivated TNBC.Jihyun KimGyubeom JangSung Hoon SimIn Hae ParkKyungtae KimCharny ParkMDPI AGarticletriple-negative breast cancercisplatin resistancemolecular subtype<i>SMARCA4</i>epithelial-to-mesenchymalHippo-YAP/TAZ pathwayNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5474, p 5474 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	triple-negative breast cancer cisplatin resistance molecular subtype <i>SMARCA4</i> epithelial-to-mesenchymal Hippo-YAP/TAZ pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	triple-negative breast cancer cisplatin resistance molecular subtype <i>SMARCA4</i> epithelial-to-mesenchymal Hippo-YAP/TAZ pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jihyun Kim Gyubeom Jang Sung Hoon Sim In Hae Park Kyungtae Kim Charny Park <i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer
description	The role of <i>SMARCA4</i>, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investigated the clinical implication and downstream regulation induced by <i>SMARCA4</i> inactivation using large-scale genome and transcriptome profiles. Additionally, <i>SMARCA4</i> was knocked out in MDA-MB-468 and MDA-MB-231 using CRISPR/Cas9 to identify gene regulation and a targetable pathway. First, we observed an increase in <i>SMARCA4</i> mutations in cisplatin resistance and metastasis in TNBC patients. Its inactivation was associated with the mesenchymal-like (MSL) subtype. Gene expression analysis showed that the epithelial-to-mesenchymal transition (EMT) pathway was activated in <i>SMARCA4</i>-deficient patients. Next, the Hippo pathway was activated in the <i>SMARCA4</i> inactivation group, as evidenced by the higher <i>CTNNB1</i>, <i>TGF-β</i>, and <i>YAP1</i> oncogene signature scores. In <i>SMARCA4</i> knockout cells, EMT was upregulated, and the cell line transcriptome changed from the SL to the MSL subtype. <i>SMARCA4</i> knockout cells showed cisplatin resistance and Hippo-YAP/TAZ target gene activation. The YAP1 inhibitor verteporfin suppressed the expression of <i>YAP1</i> target genes, and decreased cell viability and invasiveness on <i>SMARCA4</i> knockout cells. <i>SMARCA4</i> inactivation in TNBC endowed the resistance to cisplatin via EMT activation. The YAP1 inhibitor could become a novel strategy for patients with <i>SMARCA4</i>-inactivated TNBC.
format	article
author	Jihyun Kim Gyubeom Jang Sung Hoon Sim In Hae Park Kyungtae Kim Charny Park
author_facet	Jihyun Kim Gyubeom Jang Sung Hoon Sim In Hae Park Kyungtae Kim Charny Park
author_sort	Jihyun Kim
title	<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer
title_short	<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer
title_full	<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer
title_fullStr	<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer
title_full_unstemmed	<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer
title_sort	<i>smarca4</i> depletion induces cisplatin resistance by activating yap1-mediated epithelial-to-mesenchymal transition in triple-negative breast cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/098fe13511404653a3dec055bf5a64a8
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<i>SMARCA4</i> Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer

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