Long noncoding RNA LINC01578 drives colon cancer metastasis through a positive feedback loop with the NF‐κB/YY1 axis

• Published in: Molecular oncology Vol. 14; no. 12; pp. 3211 - 3233
• Main Authors: Liu, Jia, Zhan, Yang, Wang, Jiefu, Wang, Junfeng, Guo, Jiansheng, Kong, Dalu
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-12-2020; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Colon cancer; Colorectal cancer; Disease; feedback loop; Genomes; Hospitals; Kinases; long noncoding RNA; Metastases; Metastasis; Molecular modelling; NF‐κB signaling; Plasmids; Polymerase chain reaction; Proteins; Ribonucleic acid; RNA; Survival; Tumor necrosis factor-TNF; YY1; United States > US; China; NF-κB signaling; YY1; feedback loop; long noncoding RNA; metastasis; colon cancer
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12819

LINC01578 was upregulated and correlated with metastasis and prognosis in colon cancer. Nuclear factor kappa B (NF‐κB) and Yin Yang 1 (YY1) bound to LINC01578 promoter to activate LINC01578 expression. LINC01578 interacted with and recruited EZH2 to NFKBIB promoter to repress NFKBIB expression, thereby activating NF‐κB signaling. LINC01578 upregulated YY1 via activating NF‐κB. LINC01578 enhanced colon cancer liver metastasis through forming a positive feedback loop with NF‐κB/YY1.
Metastasis accounts for poor prognosis of cancers and related deaths. Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play critical roles in several types of cancer. However, which lncRNAs contribute to metastasis of colon cancer is still largely unknown. In this study, we found that lncRNA LINC01578 was correlated with metastasis and poor prognosis of colon cancer. LINC01578 was upregulated in colon cancer, associated with metastasis, advanced clinical stages, poor overall survival, disease‐specific survival, and disease‐free survival. Gain‐of‐function and loss‐of‐function assays revealed that LINC01578 enhanced colon cancer cell viability and mobility in vitro and colon cancer liver metastasis in vivo. Mechanistically, nuclear factor kappa B (NF‐κB) and Yin Yang 1 (YY1) directly bound to the LINC01578 promoter, enhanced its activity, and activated LINC01578 expression. LINC01578 was shown to be a chromatin‐bound lncRNA, which directly bound NFKBIB promoter. Furthermore, LINC01578 interacted with and recruited EZH2 to NFKBIB promoter and further repressed NFKBIB expression, thereby activating NF‐κB signaling. Through activation of NF‐κB, LINC01578 further upregulated YY1 expression. Through activation of the NF‐κB/YY1 axis, LINC01578 in turn enhanced its own promoter activity, suggesting that LINC01578 and NF‐κB/YY1 formed a positive feedback loop. Blocking NF‐κB signaling abolished the oncogenic roles of LINC01578 in colon cancer. Furthermore, the expression levels of LINC01578, NFKBIB, and YY1 were correlated in clinical tissues. Collectively, this study demonstrated that LINC01578 promoted colon cancer metastasis via forming a positive feedback loop with NF‐κB/YY1 and suggested that LINC01578 represents a potential prognostic biomarker and therapeutic target for colon cancer metastasis.