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Small protein ERSP encoded by LINC02870 promotes triple negative breast cancer progression via IRE1α/XBP1s activation

Cell Death & Differentiation volume 32, pages 1014–1025 (2025)Cite this article

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Abstract

Clinical treatment options for triple-negative breast cancer (TNBC) are currently limited to chemotherapy because of a lack of effective therapeutic targets. Recent evidence suggests that long noncoding RNAs (lncRNAs) encode bioactive peptides or proteins, thereby playing noncanonical yet significant roles in regulating cellular processes. However, the potential of lncRNA-translated products in cancer progression remains largely unknown. In this study, we identified a previously undocumented small protein encoded by the lncRNA LINC02870. This protein is localized at the endoplasmic reticulum (ER) and participates in ER stress, thus, we named it the endoplasmic reticulum stress protein (ERSP). ERSP was highly expressed in TNBC tissues, and elevated LINC02870 content was correlated with poor prognosis in TNBC patients. Loss of ERSP inhibited TNBC growth and metastasis both in vitro and in vivo. The pro-oncogenic effects of ERSP could be attributed to its selective activation of the IRE1α/XBP1s branch. ERSP enhances the unfolded protein response (UPR) by interacting with XBP1s, facilitating the nuclear accumulation of XBP1s, thereby promoting the expression of ER stress-related genes. These findings highlight the regulatory role of the lncRNA-encoded protein ERSP in ER stress and suggest that it is a potential therapeutic target for TNBC.

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Fig. 1: Identification and characterization of the LINC02870-encoded small protein ERSP.
Fig. 2: ERSP was highly expressed in TNBC tissues.
Fig. 3: ERSP knockdown inhibits the growth, migration, and invasion of TNBC cells.
Fig. 4: ERSP is located at the ER and selectively activates the IRE1α/XBP1s branch.
Fig. 5: ERSP interacts with XBP1s and increases the level of XBP1s in the nucleus.
Fig. 6: ERSP knockdown inhibits TNBC tumor growth and metastasis in mice.

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Data availability

RNA-seq data are available at the National Genomics Data Center database: https://github.com/Wangjunjian-lab/Small-protein-ERSP-encoded-by-LINC02870. The mass spectrometry data have been deposited to the ProteomeXchange Consortium via the iProX partner repository (https://www.iprox.cn) with the dataset identifier PXD048235.

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Acknowledgements

We thank all members of JJW’s lab for helpful discussions and input. This research was supported by the National Natural Science Foundation of China (82273956, 82272968); the Guangdong Basic and Applied Basic Research Foundation (2022B1515130008); the Key Research and Development Plan of Guangzhou City (202206080007); and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (No. 23ptpy36, 24xkjc016).

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Author notes

  1. These authors contributed equally: Xiaolu Wang, Qianqian Wang.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China

    Xiaolu Wang, Qianqian Wang, Hong Wang, Guodi Cai, Yana An, Peiqing Liu, Huihao Zhou, Jiantao Ye & Junjian Wang

  2. State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China

    Xiaolu Wang

  3. National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China

    Peiqing Liu, Jiantao Ye & Junjian Wang

  4. Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China

    Peiqing Liu, Jiantao Ye & Junjian Wang

  5. Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, CA, USA

    Hong-Wu Chen

  6. Special Medical Service Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510006, China

    Shufeng Ji

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Contributions

XW: conducted the protein-identification experiments, prepared the figures and wrote the original manuscript. QW: conducted the functional experiments, and prepared the figures. HW: conducted the lentiviral packaging and animal experiments. GC and YA: participated in protein expression and purification. PL and HZ: provided funding acquisition and project administration. HC: provided materials and supervision. SJ: provided funding acquisition. JY: wrote and revised the manuscript. JW: designed the experiments, funding acquisition, and supervision.

Corresponding authors

Correspondence to Shufeng Ji, Jiantao Ye or Junjian Wang.

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Animal experimental procedures and operations were approved by the Animal Welfare and Ethics Committee of Sun Yat-sen University, complied with the ARRIVE guidelines, and carried out in accordance with the National Institutes of Health guide for the care and use of Laboratory animals.

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Wang, X., Wang, Q., Wang, H. et al. Small protein ERSP encoded by LINC02870 promotes triple negative breast cancer progression via IRE1α/XBP1s activation. Cell Death Differ 32, 1014–1025 (2025). https://doi.org/10.1038/s41418-025-01443-5

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