A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

• Published in: Oncogene 2021-03, Vol.40 (9), p.1609-1627
• Main Authors: Zhu, Pengpeng, He, Fang, Hou, Yixuan, Tu, Gang, Li, Qiao, Jin, Ting, Zeng, Huan, Qin, Yilu, Wan, Xueying, Qiao, Yina, Qiu, Yuxiang, Teng, Yong, Liu, Manran
• Format: Article
• Language: English
• Subjects: 13/109; 13/89; 14/63; 38/39; 38/44; 38/61; 38/90; 631/337/384; 631/532/71; 631/67/1347; 64/60; 82/29; 82/51; Apoptosis; Binding proteins; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; c-Myc protein; Carcinogenesis - genetics; Care and treatment; Cell Biology; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Cell Self Renewal - genetics; Cell self-renewal; Development and progression; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Health aspects; Human Genetics; Humans; Hypoxia; Insulin; Internal Medicine; Medicine; Medicine & Public Health; Microenvironments; mRNA stability; Myc protein; N6-methyladenosine; Neoplastic Stem Cells - metabolism; Oncology; Proto-Oncogene Proteins c-myc - genetics; RNA Stability - genetics; RNA, Long Noncoding - genetics; RNA, Messenger - genetics; RNA-Binding Proteins - genetics; Stem cells; Tumorigenesis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01638-9

The hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.