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LncRNA NORAD is repressed by the YAP pathway and suppresses lung and breast cancer metastasis by sequestering S100P

Oncogene volume 38, pages 5612–5626 (2019)Cite this article

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Abstract

Metastasis is responsible for most cancer mortality, but its molecular mechanism has not been completely understood. In addition to coding genes and miRNAs, the contribution of long noncoding RNAs (lncRNAs) to tumor metastatic dissemination and the mechanisms controlling their expression are areas of intensive investigation. Here, we show that lncRNA NORAD is downregulated in lung and breast cancers, and that NORAD low expression in these cancer types is associated with lymph node metastasis and poor prognosis. NORAD is transcriptionally repressed by the Hippo pathway transducer YAP/TAZ-TEAD complex in conjunction with the action of NuRD complex. Functionally, NORAD elicits potent inhibitory effects on migration and invasion of multiple lung and breast cancer cell lines, and repression of NORAD expression participates in the migration- and invasion-stimulatory effects of the YAP pathway. Mechanistically, NORAD exploits its multiple repeated sequences to function as a multivalent platform for binding and sequestering S100P, thereby suppressing S100P-elicited pro-metastatic signaling network. Using cell and mouse models, we show that the S100P decoy function of NORAD suppresses lung and breast cancer migration, invasion, and metastasis. Together, our study identifies NORAD as a novel metastasis suppressor, elucidates its regulatory and functional mechanisms, and highlights its prognostic value.

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Acknowledgments

We thank Sherry Hsueh-Chi Yen and Pan-Chyr Yang for reagents, Suh-Yuen Liang for TCGA analysis, National RNAi Core Facility for shRNA constructs and CRISPR vectors and constructs, Academia Sinica Animal Core Facility for IVIS analysis, Institute of Biological Chemistry Histopathology Core Facility for tissue processing and histology, Academia Sinica Common Mass Spectrometry Facilities for MS analysis, Human Biobank, Research Center of Clinical Medicine, and Cancer Data Bank of National Cheng Kung University Hospital for patient’s specimens. This work is supported by National Health Research Institute Grant NHRI-EX107-10708BI and intramural fund from Institute of Biological Chemistry, Academia Sinica.

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Authors and Affiliations

  1. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

    Boon-Shing Tan, Min-Chi Yang, Shaifali Singh & Ruey-Hwa Chen

  2. Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan

    Min-Chi Yang & Ruey-Hwa Chen

  3. Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan

    Shaifali Singh & Ruey-Hwa Chen

  4. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan

    Shaifali Singh

  5. Genomic Research Center, Academia Sinica, Taipei, Taiwan

    Yu-Chi Chou

  6. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Hsin-Yi Chen

  7. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Ming-Yang Wang

  8. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Yi-Ching Wang

  9. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Yi-Ching Wang

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Contributions

RHC conceived the project. BST, MCY, and RHC designed experiments. BST, MCY, SS, HYC, and YCC conducted experiments. MYW and YCW provided breast and lung cancer patient specimens, respectively.

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Correspondence to Ruey-Hwa Chen.

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Tan, BS., Yang, MC., Singh, S. et al. LncRNA NORAD is repressed by the YAP pathway and suppresses lung and breast cancer metastasis by sequestering S100P. Oncogene 38, 5612–5626 (2019). https://doi.org/10.1038/s41388-019-0812-8

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