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

Leiyan Yang; Miaomiao Wang; Ya Wang; Yong Zhu; Jiarui Wang; Mingming Wu; Qianying Guo; Xinghua Han; Vijay Pandey; Zhengsheng Wu; Peter E Lobie; Tao Zhu

doi:10.1038/s41388-024-02972-y

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

Oncogene. 2024 Apr;43(17):1249-1262. doi: 10.1038/s41388-024-02972-y. Epub 2024 Feb 28.

Authors

Leiyan Yang^#^{1

2}, Miaomiao Wang^#^{1

2}, Ya Wang³, Yong Zhu⁴, Jiarui Wang^{1

2}, Mingming Wu^{1

2}, Qianying Guo⁵, Xinghua Han¹, Vijay Pandey⁶, Zhengsheng Wu⁵, Peter E Lobie^{7

8}, Tao Zhu^{9

10

11}

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.
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.
³ Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China.
⁴ Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, Anhui, China.
⁵ Department of Pathology, Anhui Medical University, Hefei, 230032, Anhui, China.
⁶ Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
⁷ Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China. pelobie@sz.tsinghua.edu.cn.
⁸ Shenzhen Bay Laboratory, Shenzhen, 518055, China. pelobie@sz.tsinghua.edu.cn.
⁹ 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. zhut@ustc.edu.cn.
¹⁰ Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China. zhut@ustc.edu.cn.
¹¹ Shenzhen Bay Laboratory, Shenzhen, 518055, China. zhut@ustc.edu.cn.

^# Contributed equally.

PMID: 38418543
DOI: 10.1038/s41388-024-02972-y

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.

Abstract

Grants and funding