期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：39
DOI：10.1073/pnas.2117988119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The multisubunit ATPase-dependent SWI/SNF complex plays an important role in chromatin remodeling. Large numbers of SWI/SNF subunit mutations have been identified in large variety of human cancers, suggesting that they function against tumorigenesis. Here we report long noncoding RNA TGFB2-AS1 correlates with prognosis in triple-negative breast cancer, the most aggressive cluster of all breast cancers. Especially, we show that TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF complex, and blocks the complex to approach its target promoters both in cis and in trans, thus inhibiting the expression of the target genes, TGFB2 and SOX2, eventually leading to the inhibition of breast cancer progression. These findings shed light on understanding regulation and roles of the SWI/SNF complex in carcinogenesis.
Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells in vitro and dramatically decreases tumorigenic frequency and lung metastasis in vivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, and results in transcriptional repression of its target genes including
TGFB2 and
SOX2 in an
in cis or
in trans way, leading to inhibition of transforming growth factor β (TGFβ) signaling and BCSC characteristics. In line with this, TGFB2-AS1 overexpression in an orthotopic TNBC mouse model remarkably abrogates the enhancement of tumor growth and lung metastasis endowed by TGFβ2. Furthermore, combined prognosis analysis of TGFB2-AS1 and TGFβ2 in TNBC patients shows that high TGFB2-AS1 and low TGFβ2 levels are correlated with better outcome. These findings demonstrate a key role of TGFB2-AS1 in inhibiting disease progression of TNBC based on switching the cancer cell fate of TNBC and also shed light on the treatment of TNBC patients.
关键词：enTGFB2-AS1cancer stem-like cellSWI/SNF complexTGFβ signalingtriple-negative breast cancer
