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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer
Zhaoran Sun1, Zhongkun Wang2, Yirao Zhang1
1Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical University, Xuzhou, China.
Abstract:
SWI/SNF chromatin remodeling complexes play a key role in gene transcription as epigenetic regulators and are typically considered to act as tumor suppressors in cancers. Compared to other cancer-related components of the SWI/SNF complex, research on SMARCC2, a component of the initial BAF core, has been relatively limited. This study aimed to elucidate the role of SMARCC2 in breast cancer by employing various in vitro and in vivo methods including cell proliferation assays, mammosphere formation, and xenograft models, complemented by RNA-seq, ATAC-seq, and ChIP analyses. The results showed that SMARCC2 silencing surprisingly led to the suppression of breast tumorigenesis, indicating a pro-tumorigenic function for SMARCC2 in breast cancer, which contrasts with the roles of other SWI/SNF subunits. In addition, SMARCC2 depletion reduces cancer stem cell features of breast cancer cells. Mechanistic study showed that SMARCC2 silencing downregulated the oncogenic Ras-PI3K signaling pathway, likely by directly regulating the chromatin accessibility of the enhancers of the key genes such as PIK3CB. Together, these results expand our understanding of the SWI/SNF complex's role in cancer development and identify SMARCC2 as a promising new target for breast cancer therapies.
Insights
SMARCC2, a component of the SWI/SNF complex, surprisingly promotes breast cancer growth and stem cell features. Its depletion suppresses tumors by downregulating the Ras-PI3K pathway, identifying SMARCC2 as a potential therapeutic target.
Area of Science:
- Epigenetics
- Cancer Biology
- Chromatin Remodeling
Background:
- SWI/SNF chromatin remodeling complexes are epigenetic regulators crucial for gene transcription.
- These complexes are generally considered tumor suppressors in cancer.
- Research on SMARCC2, a core BAF component, is limited compared to other SWI/SNF subunits.
Purpose of the Study:
- To investigate the role of SMARCC2 in breast cancer.
- To determine if SMARCC2 acts as a tumor suppressor or oncogene in breast cancer.
Main Methods:
- In vitro and in vivo assays including cell proliferation, mammosphere formation, and xenograft models.
- Genomic analyses such as RNA-seq, ATAC-seq, and ChIP.
- Investigation of the Ras-PI3K signaling pathway.
Main Results:
- SMARCC2 silencing suppressed breast tumorigenesis, indicating a pro-tumorigenic role.
- SMARCC2 depletion reduced cancer stem cell characteristics.
- SMARCC2 silencing downregulated the Ras-PI3K pathway, potentially via direct regulation of enhancer chromatin accessibility for genes like PIK3CB.
Conclusions:
- SMARCC2 exhibits a pro-tumorigenic function in breast cancer, contrasting with other SWI/SNF subunits.
- SMARCC2 plays a role in maintaining cancer stem cell features.
- SMARCC2 is a potential therapeutic target for breast cancer treatment.
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