LINC00882, transcriptionally activated by CEBP-β and post-transcriptionally stabilized by METTL14-mediated m6A modification, exerts tumorigenesis by promoting PABPC1-mediated stabilization of ELK3 mRNA

Abstract

Breast cancer (BC) is the most common malignant tumor in women, and the majority of BC-related deaths are due to tumor metastasis. There is emerging evidence for the role of long noncoding RNAs (lncRNAs) in tumor progression. Nevertheless, lncRNAs that drive metastasis in patients with BC and the underlying mechanisms of lncRNAs are still largely elusive. In this study, we showed that LINC00882 was highly expressed in metastatic BC tissues, and a receiver operating characteristic (ROC) curve was able to distinguish well between BC cases with lymph node metastasis (LNM) and those without LNM. Functionally, LINC00882 promoted BC invasion and metastasis in vitro and in vivo. Mechanistically, at the transcriptional level, CEBP-β could bind directly to the LINC00882 promoter region and activate its transcription. Moreover, at the posttranscriptional level, m6A modification of LINC00882 mediated by methyltransferase-like 14 (METTL14) promoted its expression via an IGF2BP2-dependent pathway. Furthermore, 514–615 nucleotides of LINC00882 could directly interact with poly (A) binding protein cytoplasmic 1 (PABPC1) and promote the interaction between PABPC1 and ELK3 mRNA, thereby stabilizing ELK3 mRNA and enhancing the ELK3 protein level. E-cadherin expression was suppressed via ELK3-mediated transcription inhibition, subsequently activating epithelial–mesenchymal transition to promote BC metastasis. These results highlight the role of LINC00882 in BC, and LINC00882 may be a diagnostic and therapeutic target for BC.