<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: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/098fe13511404653a3dec055bf5a64a8 |
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| Sumario: | 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. |
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