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LINC00460-FUS-MYC feedback loop drives breast cancer metastasis and doxorubicin resistance

Oncogene volume 43, pages 1249–1262 (2024)Cite this article

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Abstract

Therapeutic resistance and metastasis largely contribute to mortality from breast cancer and therefore understanding the underlying mechanisms of such remains an urgent challenge. By cross-analysis of TCGA and GEO databases, LINC00460 was identified as an oncogenic long non-coding RNA, highly expressed in Doxorubicin resistant breast cancer. LINC00460 was further demonstrated to promote stem cell-like and epithelial-mesenchymal transition (EMT) characteristics in breast cancer cells. LINC00460 interacts with FUS protein with consequent enhanced stabilization, which further promotes MYC mRNA maturation. LINC00460 expression was transcriptionally enhanced by c-MYC protein, forming a positive feedback loop to promote metastasis and Doxorubicin resistance. LINC00460 depletion in Doxorubicin-resistant breast cancer cells restored sensitivity to Doxorubicin and increased the efficacy of c-MYC inhibitor therapy. Collectively, these findings implicate LINC00460 as a promising prognostic biomarker and potential therapeutic target to overcome Doxorubicin resistance in breast cancer.

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Fig. 1: Elevated expression of LINC00460 in Doxorubicin-resistant BC is associated with poor prognosis.
Fig. 2: LINC00460 regulates CSC-like characteristics and promotes Doxorubicin resistance in breast cancer cells.
Fig. 3: LINC00460 regulates EMT and promotes metastasis.
Fig. 4: LINC00460 interacts with and stabilizes FUS.
Fig. 5: LINC00460 depends on FUS to promote Doxorubicin resistance and metastasis.
Fig. 6: LINC00460 tethered FUS regulates MYC mRNA maturation.
Fig. 7: Positive feedback loop between MYC and LINC00460 contributes to Doxorubicin resistance in breast cancer.

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Acknowledgements

The authors greatly thank Dr. Li Bai (USTC, China) for providing HEK-293T cell lines, Dr. Suling Liu (Fudan University, China) for providing SUM149 cell lines, Dr. Ping Gao (SCUT, China) for providing pCDH-c-MYC plasmid, Dr. Huafeng Zhang for providing pSin-puro vector, Dr. Rui Sun for providing lentivirus production plasmids, Dr. Yide Mei for providing HA-ub plasmid, and Dr. Liting Qian for providing pHBLV-ZsGreen plasmid, respectively. This work was supported by the National Natural Science Foundation of China (82173254, 82373152, 82172618, 82103531), the Fundamental Research Funds for the Central Universities (YD9100002010), the Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYPY2022020) and Shenzhen Bay Scholars Program; the Shenzhen Key Laboratory of Innovative Oncotherapeutics (ZDSYS20200820165400003) (Shenzhen Science and Technology Innovation Commission), China; Shenzhen Development and Reform Commission Subject Construction Project ([2017]1434), China; Overseas Research Cooperation Project (HW2020008) (Tsinghua Shenzhen International Graduate School), China; Universities Stable Funding Key Projects (WDZC20200821150704001); The Shenzhen Bay Laboratory, Oncotherapeutics (21310031), China; TBSI Faculty Start-up Funds, China; the National Natural Science Foundation of China (Grant No. 82172618).

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  1. These authors contributed equally: Leiyan Yang, Miaomiao Wang.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China

    Leiyan Yang, Miaomiao Wang, Jiarui Wang, Mingming Wu, Xinghua Han & Tao Zhu

  2. Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China

    Leiyan Yang, Miaomiao Wang, Jiarui Wang, Mingming Wu & Tao Zhu

  3. Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China

    Ya Wang

  4. Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, Anhui, China

    Yong Zhu

  5. Department of Pathology, Anhui Medical University, Hefei, 230032, Anhui, China

    Qianying Guo & Zhengsheng Wu

  6. Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China

    Vijay Pandey & Peter E. Lobie

  7. Shenzhen Bay Laboratory, Shenzhen, 518055, China

    Peter E. Lobie & Tao Zhu

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Contributions

LY, PEL and TZ conceived the project and designed the experiments. LY, MW, YW, JW, and YZ collected most of the data. LY, PEL and TZ analyzed the results. ZW, Q,G and XH provided breast cancer patient samples, LY, MW, VP, PEL, and TZ wrote and revised the manuscript.

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Correspondence to Peter E. Lobie or Tao Zhu.

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Yang, L., Wang, M., Wang, Y. et al. LINC00460-FUS-MYC feedback loop drives breast cancer metastasis and doxorubicin resistance. Oncogene 43, 1249–1262 (2024). https://doi.org/10.1038/s41388-024-02972-y

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