Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA

• Published in: Cell death and differentiation 2019-11, Vol.26 (11), p.2329-2343
• Main Authors: Wang, Min, Mao, Chao, Ouyang, Lianlian, Liu, Yating, Lai, Weiwei, Liu, Na, Shi, Ying, Chen, Ling, Xiao, Desheng, Yu, Fenglei, Wang, Xiang, Zhou, Hu, Cao, Ya, Liu, Shuang, Yan, Qin, Tao, Yongguang, Zhang, Bin
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/31; 13/89; 38/1; 38/77; 42/109; 42/44; 42/89; 631/67/1612/1350; 631/67/1857; 82/1; A549 Cells; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Line, Tumor; Cell Proliferation - genetics; Cell Survival - genetics; Cystathionine beta-Synthase - metabolism; DNA helicase; ELAV-Like Protein 1 - genetics; ELAV-Like Protein 1 - metabolism; Ferroptosis; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic - genetics; Gene regulation; Gene Regulatory Networks - genetics; Humans; Life Sciences; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mice, Nude; MicroRNAs; MicroRNAs - genetics; miRNA; Neoplasm Transplantation; Nucleotides; p53 Protein; Post-transcription; RNA, Long Noncoding - genetics; RNA, Messenger - genetics; RNA-binding protein; Signal transduction; Stem Cells; Transplantation, Heterologous; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-019-0304-y

The regulatory loop between long noncoding RNAs (lncRNAs) and microRNAs has a dynamic role in transcriptional and translational regulation, and is involved in cancer. However, the regulatory circuitry between lncRNAs and microRNAs in tumorigenesis remains elusive. Here we demonstrate that a nuclear lncRNA LINC00336 is upregulated in lung cancer and functions as an oncogene by acting as a competing endogenous RNA (ceRNAs). LINC00336 bound RNA-binding protein ELAVL1 (ELAV-like RNA-binding protein 1) using nucleotides 1901–2107 of LINC00336 and the RRM interaction domain and key amino acids (aa) of ELAVL1 (aa 101–213), inhibiting ferroptosis. Moreover, ELAVL1 increased LINC00336 expression by stabilizing its posttranscriptional level, whereas LSH (lymphoid-specific helicase) increased ELAVL1 expression through the p53 signaling pathway, further supporting the hypothesis that LSH promotes LINC00336 expression. Interestingly, LINC00336 served as an endogenous sponge of microRNA 6852 (MIR6852) to regulate the expression of cystathionine-β-synthase (CBS), a surrogate marker of ferroptosis. Finally, we found that MIR6852 inhibited cell growth by promoting ferroptosis. These data show that the network of lncRNA and ceRNA has an important role in tumorigenesis and ferroptosis.