TGF-β plays a central role in mediating epithelial-mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF-β-induced EMT is NF-κB-dependent in various cancer types. However, it is largely unclear if NF-κB mediates TGF-β-induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF-β activates the NF-κB pathway. Inhibition of NF-κB signaling markedly abrogates TGF-β-induced EMT. By studying the regulatory mechanism of TGF-β-induced NF-κB signaling, we found that lncRNA NKILA was upregulated by TGF-β and was essential for the negative feedback regulation of the NF-κB pathway. Accordingly, overexpression of NKILA significantly reduced TGF-β-induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA-mediated negative feedback affects TGF-β-induced NF-κB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT.
Long Intergenic non-coding RNAs (lincRNAs) expressed in tissue-specificity model are involved in a variety of tumor biological processes. Super enhancers (SEs) have been shown to drive the expression of genes including lincRNAs that control cell identity and the development of cancer. However, the role of super-enhancer-driven lincRNAs in luminal type breast cancer (BC) is poorly understood. Here we identified a lincRNA, BCSL1, was uniquely up-regulated in BC tumor tissues and cell lines. ChIP-sequencing and Hi-C analysis manifested that BCSL1 was directly regulated by the luminal subtype specific SEs in BC cells. Nuclear plasma separation assay and FISH test showed that BCSL1 slightly more located in the cytoplasm than the nucleus of MCF7 cells. Knocking down of BCSL1 significantly inhibited the proliferation, colony formation and apoptosis of BC cells, and the cell cycle switching from G1 stage to S stage. Overexpression of BCSL1 significantly increased their proliferation, colony formation and apoptosis. Mechanistically, RNA pulldown, Mass spectrometry and RNA-sequencing indicated BCSL1 may be involved in the development of luminal BC by participating in apoptosis-related pathways.In summary, we identified a lincRNA, BCSL1, that is uniquely increased in breast cancer. Increased expression of BCSL1 promotes the proliferation, colony formation and apoptosis of luminal breast cancer cells. BCSL1 might be developed as a biomarker of luminal breast cancer patients. This work was supported by the National Natural Science Foundation of China (81803636 and 81972658), the Natural Science Foundation of Guangdong Province (2018A0303130329). Citation Format: Xiaoqing Yuan, Li Peng, Jianing Chen, Xiuying Cui, Yujie Liu, Erwei Song. Super enhancer-associated lincRNA BCSL1 promotes the development of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4825.
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