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

Min Wang,Yating Liu,Ying Shi,Xiang Wang,Desheng Xiao,Ya Cao,Qin Yan,Lianlian Ouyang,Yongguang Tao,Chao Mao,Na Liu,Ling Chen,Fenglei Yu,Shuang Liu,Hu Zhou,Weiwei Lai,Bin Zhang

doi:10.1038/s41418-019-0304-y

Abstract

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.

Highlights

These authors contributed : Min Wang, Chao MaoEdited by S
To validate long noncoding RNAs (lncRNAs) that might be regulated by Lymphoid-specific helicase (LSH), LSH expression levels were detected in lung cancer cell lines, and were overexpressed in H358 and PC9 cell lines and knocked down in A549 cell line by using lentivirus
The nuclear localization of LINC00336 was confirmed by subcellular fractionation analyses of H358, SPC-A-1, PC9, and A549 cells (Supplementary Fig. 1g-j), suggesting that LINC00336 may perform its biological functions in the nucleus

Summary

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Epigenetic modifiers, including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), have important roles in the development and progression of NSCLC [2, 3]. Sponging activity indicates that coding and noncoding RNAs may be a component of common regulatory circuitries in which they control one another through their ability to compete for miRNA binding, supporting the term “competing endogenous RNA” (ceRNA) [15]. Ferroptosis, a newly discovered mode of nonapoptotic cell death, involves metabolic dysfunction that results in intracellular metabolic process glutaminolysis and the production of iron-dependent reactive oxygen species (ROS), the iron carrier protein transferrin, and mitochondrial superoxide, as well as membrane potential decrease and the formation of other related regulators such as p53 [32,33,34,35,36]. We investigate LINC00336associated epigenetic regulation in ferroptosis and tumorigenicity in lung cancer

Results

Discussion

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