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LncRNA SLC26A4-AS1 suppresses the MRN complex-mediated DNA repair signaling and thyroid cancer metastasis by destabilizing DDX5

Oncogene volume 39, pages 6664–6676 (2020)Cite this article

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Abstract

Lymph node metastasis is the major adverse feature for recurrence and death of thyroid cancer patients. To identify lncRNAs involved in thyroid cancer metastasis, we systemically screened differentially expressed lncRNAs in lymph node metastasis, thyroid cancer, and normal tissues via RNAseq. We found that lncRNA SLC26A4-AS1 was continuously, significantly down-regulated in normal tissues, thyroid cancer, and lymph node metastasis specimens. Low SLC26A4-AS1 levels in tissues were significantly associated with poor prognosis of thyroid cancer patients. LncRNA SLC26A4-AS1 markedly inhibited migration, invasion, and metastasis capability of cancer cells in vitro and in vivo. Intriguingly, SLC26A4-AS1 could simultaneously interact with DDX5 and the E3 ligase TRIM25, which promoting DDX5 degradation through the ubiquitin-proteasome pathway. In particular, SLC26A4-AS1 inhibited expression of multiple DNA double-strand breaks (DSBs) repair genes, especially genes coding proteins in the MRE11/RAS50/NBS1 (MRN) complex. Enhanced interaction between DDX5 and transcriptional factor E2F1 due to silencing of SLC26A4-AS1 promoted binding of the DDX5–E2F1 complex at promoters of the MRN genes and, thus, stimulate the MRN/ATM dependent DSB signaling and thyroid cancer metastasis. Our study uncovered new insights into the biology driving thyroid cancer metastasis and highlights potentials of lncRNAs as future therapeutic targets again cancer metastasis.

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Fig. 1: LncRNA SLC26A4-AS1 was continuously down-regulated in normal tissues, thyroid cancer, and lymph node metastasis specimens.
Fig. 2: LncRNA SLC26A4-AS1 suppressed metastasis of thyroid cancer cells in vitro and in vivo.
Fig. 3: LncRNA SLC26A4-AS1 interacted with DDX5 and accelerated its degradation.
Fig. 4: SLC26A4-AS1 promoted interactions between DDX5 and the E3 ligase TRIM25.
Fig. 5: Silencing of lncRNA SLC26A4-AS1 enhanced activities of the DDX5–E2F1 transfactor complex to promote transcription of the MRN genes.
Fig. 6: LncRNA SLC26A4-AS1 suppressed DSB repair signaling.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (31671300, 31871306, 81702276); Taishan Scholars Program of Shandong Province (tsqn20161060); Program of Science and Technology for the youth innovation team in universities of Shandong Province (2020KJL001); Natural Science Foundation of Shandong Province (ZR2016HQ48, ZR2019LZL011). The authors would like to thank many individuals who participated in the study.

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  1. Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Jupeng Yuan, Yemei Song, Wenting Pan, Yankang Li, Yeyang Xu, Mengyu Xie, Yue Shen, Nasha Zhang, Jiandong Liu, Hui Hua, Bowen Wang & Ming Yang

  2. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

    Yankang Li, Yeyang Xu, Mengyu Xie, Yue Shen & Bowen Wang

  3. Department of Head and Neck Surgery, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Changming An

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Yuan, J., Song, Y., Pan, W. et al. LncRNA SLC26A4-AS1 suppresses the MRN complex-mediated DNA repair signaling and thyroid cancer metastasis by destabilizing DDX5. Oncogene 39, 6664–6676 (2020). https://doi.org/10.1038/s41388-020-01460-3

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