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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

Oncogene volume 44, pages 363–377 (2025)Cite this article

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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.

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Fig. 1: LINC00882 is upregulated in BC tissues with lymph node metastasis and histone acetylation and CEBP-β synergistically activates LINC00882 transcription in BC cells.
Fig. 2: METTL14-mediated m6A modification promotes LINC00882 expression via IGF2BP2-dependent stabilization of RNA.
Fig. 3: LINC00882 promotes an aggressive phenotype in vitro and in vivo.
Fig. 4: LINC00882 directly binds the PABPC1.
Fig. 5: LINC00882 promotes the stabilization of ELK3 mRNA via PABPC1.
Fig. 6: LINC00882 activates EMT via PABPC1-dependent stabilization of ELK3 mRNA.
Fig. 7

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Data availability

The data that support the findings of this study are available on request from the corresponding author upon reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 82273378, 82103564 and 82372975), Natural Science Foundation of Shandong Province (Grant No. ZR2020QH223), Future Plans for Shandong University Young Scholars and “Youth innovation program” of College of Shandong province.

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  1. These authors contributed equally: Zhao-Xin Gao, Chun-Lan Li.

Authors and Affiliations

  1. Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China

    Zhao-Xin Gao, Chun-Lan Li, Han Zhang, Guo-Hao Zhang, Yu Zhang, Xiang-Yu Guo, Zhi-Yuan Tang, Peng Gao & Hai-Ting Liu

  2. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medicine, Shandong University, Jinan, 250012, Shandong, China

    Zhao-Xin Gao, Han Zhang, Zhi-Yuan Tang, Peng Gao & Hai-Ting Liu

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Contributions

GP and LHT were involved in the conception and design of this manuscript; GZX, LCL, ZH, ZGH, ZY, GXY and TZY collected the clinical tumor samples; GP and LHT performed data analysis and interpretation; and GZX and LCL wrote the manuscript. All authors were involved in writing the paper and had final approval of the final manuscript.

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Correspondence to Peng Gao or Hai-Ting Liu.

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Fresh BC tissues were obtained with informed patient consent and approval from the Qilu Hospital of Shandong University, and the Research Ethics Committee of Shandong University. Patients’ privacy has been fully protected. Animal experiments were conducted according to the Guidelines for Animal Health and Use (Ministry of Science and Technology, China, 2006), and were approved by the Committee for Animal Protection of Shandong University.

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Gao, ZX., Li, CL., Zhang, H. et al. 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. Oncogene 44, 363–377 (2025). https://doi.org/10.1038/s41388-024-03225-8

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