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LncRNA LY6E-DT and its encoded metastatic-related protein play oncogenic roles via different pathways and promote breast cancer progression

Cell Death & Differentiation volume 31, pages 188–202 (2024)Cite this article

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Abstract

Abnormal long noncoding RNA (lncRNA) expression plays an important role in tumor invasion and metastasis. Here, we show that lncRNA LY6E divergent transcript (LY6E-DT) levels are increased in breast cancer (BC) tissues. Transcription factor SP3 binds directly to the LY6E-DT promoter, activating its transcription. Moreover, LY6E-DT N6-methyladenosine modification by methyltransferase-like protein 14 (METTL14) promotes its expression, dependent on the “reader” insulin-like growth factor 2 mRNA binding protein 1(IGF2BP1)-dependent pathway. Notably, we discovered that the lncRNA LY6E-DT encodes a conserved 153-aa protein, “Metastatic-Related Protein” (MRP). Both LY6E-DT and MRP promote BC invasion and metastasis, and MRP expression could distinguish BC patients with lymph node metastasis from those without. Mechanistically, MRP binds heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC), enhancing the interaction between HNRNPC and epidermal growth factor receptor (EGFR) mRNA, increasing EGFR mRNA stability and protein expression and subsequently activating the phosphatidylinositol 3‑kinase/protein kinase B signaling (PI3K) pathway. LncRNA LY6E-DT promotes the interaction between Y box binding protein 1 (YBX1) and importin α1 and increases YBX1 protein entry into the nucleus, where it transcriptionally activates zinc finger E-box-binding homeobox 1(ZEB1). Our findings uncover a novel regulatory mechanism underlying BC invasion orchestrated by LY6E-DT and its encoded MRP.

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Fig. 1: LY6E-DT levels are increased in Metastatic BC tissues and LY6E-DT was transcriptionally activated by SP3.
Fig. 2: LY6E-DT was post-transcriptionally stabilized by METTL14-mediated m6A modification.
Fig. 3: LY6E-DT encodes a 153-amino-acid protein.
Fig. 4: MRP, and lncRNA LY6E-DT itself, promote BC invasion.
Fig. 5: MRP protein interacts with HNRNPC to promote EGFR stability and activate EGFR signaling pathway.
Fig. 6: LY6E-DT interacts with YBX1 protein to mediate the entry of YBX1 into the nucleus.
Fig. 7: LY6E-DT/YBX1 complex initiates ZEB1 expression.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. Microarray data were deposited in NCBI Gene Expression Omnibus (GEO, GSE225812 and GSE226696).

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81872362, 82273378, 82103564 and 82372975), and Natural Science Foundation of Shandong Province (Grant No. ZR2020QH223) and Future Plans for Shandong University Young Scholars.

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Authors and Affiliations

  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences and Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China

    Hai-Ting Liu, Zhao-Xin Gao, Xiang-Yu Guo, Chun-Lan Li, Han Zhang, Rui-Nan Zhao, Duan-Bo Shi, Wen-Jie Zhu & Peng Gao

  2. Department of Pancreatic Surgery, General Surgery, Qi Lu Hospital of Shandong University, Jinan, Shandong, 250012, China

    Feng Li

  3. Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China

    Yuan Liu

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Contributions

PG performed the conception and design of this manuscript. HTL, ZXG, FL, XYG, CLL, HZ, RNZ, YL and DBS collected clinical tumor samples. HTL and PG performed data analysis and interpretation. HTL, WJZ and PG performed the manuscript writing. All authors were involved in writing the paper and had final approval of the final manuscript.

Corresponding authors

Correspondence to Wen-Jie Zhu or Peng Gao.

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The authors declare no competing interests.

Ethics

Fresh BC and normal breast tissues were collected from the Qilu Hospital of Shandong University, which was approved by the Research Ethics Committee of Shandong University. All participants have informed consent and their privacy has been fully protected. All of the animal experiments were conducted according to the Guidelines for Animal Health and Use (Ministry of Science and Technology, China, 2006). Animal experiments were approved by the Committee for Animal Protection of Shandong University.

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Liu, HT., Gao, ZX., Li, F. et al. LncRNA LY6E-DT and its encoded metastatic-related protein play oncogenic roles via different pathways and promote breast cancer progression. Cell Death Differ 31, 188–202 (2024). https://doi.org/10.1038/s41418-023-01247-5

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