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.
摘要：
SWI/SNF染色质重塑复合物作为表观遗传调节因子在基因转录中起关键作用，通常被认为在癌症中充当肿瘤抑制因子。与SWI/SNF复合物的其他癌症相关成分相比，对SMARCC2的研究，SMARCC2是初始BAF核心的组成部分，相对有限。本研究旨在通过采用各种体外和体内方法，包括细胞增殖试验，阐明SMARCC2在乳腺癌中的作用。乳腺球的形成,和异种移植模型，由RNA-seq补充，ATAC-seq,和ChIP分析。结果表明，SMARCC2沉默令人惊讶地导致乳腺肿瘤发生的抑制，表明SMARCC2在乳腺癌中具有促瘤功能，这与其他SWI/SNF亚基的作用形成鲜明对比。此外,SMARCC2消耗减少乳腺癌细胞的癌症干细胞特征。机制研究表明SMARCC2沉默下调致癌Ras-PI3K信号通路,可能是通过直接调节关键基因如PIK3CB的增强子的染色质可及性。一起,这些结果扩大了我们对SWI/SNF复合物在癌症发展中的作用的理解,并确定SMARCC2是乳腺癌治疗的有希望的新靶点.
