Article | Published:

LINC01638 lncRNA activates MTDH-Twist1 signaling by preventing SPOP-mediated c-Myc degradation in triple-negative breast cancer

Oncogene (2018) | Download Citation

Abstract

Breast cancer is a heterogeneous disease, and triple-negative breast cancer (TNBC) continues to be a serious health problem. The potential involvement of lncRNAs in TNBC progression remains unexplored. Here, we demonstrated that LINC01638 is highly expressed in TNBC tissues and cells. LINC01638 maintains the mesenchymal traits of TNBC cells, including an enriched epithelial-mesenchymal transition (EMT) signature and cancer stem cell-like state. LINC01638 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. LINC01638 overexpression predicts a poor outcome of breast cancer patients. Mechanistically, LINC01638 interacts with c-Myc to prevent SPOP-mediated c-Myc ubiquitination and degradation. C-Myc transcriptionally enhances MTDH (metadherin) expression and subsequently activates Twist1 expression to induce EMT. Our findings describe LINC01638-mediated signal transduction and highlight the crucial role of LINC01638 in TNBC progression.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. Cancer J Clin. 2016;66:7–30.

  2. 2.

    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

  3. 3.

    Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12:R68.

  4. 4.

    Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.

  5. 5.

    Podo F, Buydens LM, Degani H, Hilhorst R, Klipp E, Gribbestad IS, et al. Triple-negative breast cancer: present challenges and new perspectives. Mol Oncol. 2010;4:209–29.

  6. 6.

    Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, et al. Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell. 2014;25:210–25.

  7. 7.

    Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011;1:391–407.

  8. 8.

    Lin A, Li C, Xing Z, Hu Q, Liang K, Han L, et al. The LINK-A lncRNA activates normoxic HIF1alpha signalling in triple-negative breast cancer. Nat Cell Biol. 2016;18:213–24.

  9. 9.

    Lee JT. Epigenetic regulation by long noncoding RNAs. Science. 2012;338:1435–9.

  10. 10.

    Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

  11. 11.

    Luo M, Jeong M, Sun D, Park HJ, Rodriguez BA, Xia Z, et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell. 2015;16:426–38.

  12. 12.

    Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

  13. 13.

    Guttman M, Rinn JL. Modular regulatory principles of large non-coding RNAs. Nature. 2012;482:339–46.

  14. 14.

    Booy EP, McRae EK, Koul A, Lin F, McKenna SA. The long non-coding RNA BC200 (BCYRN1) is critical for cancer cell survival and proliferation. Mol Cancer. 2017;16:109.

  15. 15.

    Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81.

  16. 16.

    Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015;16:413–25.

  17. 17.

    Jiang Z, Slater CM, Zhou Y, Devarajan K, Ruth KJ, Li Y, et al. LincIN, a novel NF90-binding long non-coding RNA, is overexpressed in advanced breast tumors and involved in metastasis. Breast Cancer Res. 2017;19:62.

  18. 18.

    Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteom. 2014;13:397–406.

  19. 19.

    Liang Y, Hu J, Li J, Liu Y, Yu J, Zhuang X, et al. Epigenetic activation of TWIST1 by MTDH promotes cancer stem-like cell traits in breast cancer. Cancer Res. 2015;75:3672–80.

  20. 20.

    Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB. Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA. 2006;103:17390–5.

  21. 21.

    Geng C, Kaochar S, Li M, Rajapakshe K, Fiskus W, Dong J, et al. SPOP regulates prostate epithelial cell proliferation and promotes ubiquitination and turnover of c-MYC oncoprotein. Oncogene. 2017;36:4767–77.

  22. 22.

    Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307.

  23. 23.

    Flynn RA, Chang HY. Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell. 2014;14:752–61.

  24. 24.

    Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC: clinical significance. Adv Cancer Res. 2013;120:39–74.

  25. 25.

    Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell. 2004;5:365–74.

  26. 26.

    Blanco MA, Aleckovic M, Hua Y, Li T, Wei Y, Xu Z, et al. Identification of staphylococcal nuclease domain-containing 1 (SND1) as a Metadherin-interacting protein with metastasis-promoting functions. J Biol Chem. 2011;286:19982–92.

  27. 27.

    Yoo BK, Chen D, Su ZZ, Gredler R, Yoo J, Shah K, et al. Molecular mechanism of chemoresistance by astrocyte elevated gene-1. Cancer Res. 2010;70:3249–58.

  28. 28.

    Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC: signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Adv Cancer Res. 2013;120:75–111.

  29. 29.

    Wan L, Lu X, Yuan S, Wei Y, Guo F, Shen M, et al. MTDH-SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors. Cancer Cell. 2014;26:92–105.

  30. 30.

    Liu L, Wu J, Ying Z, Chen B, Han A, Liang Y, et al. Astrocyte elevated gene-1 upregulates matrix metalloproteinase-9 and induces human glioma invasion. Cancer Res. 2010;70:3750–9.

  31. 31.

    Hu G, Wei Y, Kang Y. The multifaceted role of MTDH/AEG-1 in cancer progression. Clin Cancer Res. 2009;15:5615–20.

  32. 32.

    Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 2009;15:9–20.

  33. 33.

    Ni M, Chen Y, Fei T, Li D, Lim E, Liu XS, et al. Amplitude modulation of androgen signaling by c-MYC. Genes Dev. 2013;27:734–48.

  34. 34.

    Cho KB, Cho MK, Lee WY, Kang KW. Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett. 2010;293:230–9.

  35. 35.

    Cho MH, Park JH, Choi HJ, Park MK, Won HY, Park YJ, et al. DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression. Nat Commun. 2015;6:7821.

  36. 36.

    Yin J, Zheng G, Jia X, Zhang Z, Zhang W, Song Y, et al. A Bmi1-miRNAs cross-talk modulates chemotherapy response to 5-fluorouracil in breast cancer cells. PLoS ONE. 2013;8:e73268.

  37. 37.

    Zheng G, Zhang Z, Liu H, Xiong Y, Luo L, Jia X, et al. HSP27-mediated extracellular and intracellular signaling pathways synergistically confer chemo-resistance in squamous cell carcinoma of tongue. Clin Cancer Res. 2017;24:1163–75.

Download references

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China: No. 81672616 (GZ), No. 81402196 (GZ), No. 81772961 (HT), No. 81401989 (NL) and No. 81772825 (HL); supported by grants from Guangdong Natural Science Funds for Distinguished Young Scholars: No. 2016A030306003 (GZ) and Guangdong Natural Science Funds: No. 2017A030313867 (GZ); supported by grants from Science and Technology Program of Guangzhou: No. 201710010100 (GZ) and Guangzhou Municipal University Scientific Research project: 1201610027 (GZ).

Author information

Author notes

  1. These authors contributed equally: Liyun Luo, Hailin Tang.

Affiliations

  1. Affiliated Cancer Hospital & Institute of Guangzhou Medical University; Guangzhou Key Laboratory of “Translational Medicine on Malignant Tumor Treatment”; Protein Modification and Degradation Lab, Guangzhou Medical University, Hengzhigang Road 78#, 510095, Guangzhou, Guangdong, China

    • Liyun Luo
    • , Li Ling
    • , Nan Li
    • , Xiaoting Jia
    • , Zhijie Zhang
    • , Xiaorong Wang
    • , Lejuan Shi
    • , Jiang Yin
    • , Ni Qiu
    • , Hao Liu
    • , Ying Song
    • , Kai Luo
    • , Hongsheng Li
    • , Zhimin He
    •  & Guopei Zheng
  2. Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Dongfeng Road 651 E, 510060, Guangzhou, Guangdong, China

    • Hailin Tang
    •  & Xiaoming Xie

Authors

  1. Search for Liyun Luo in:

  2. Search for Hailin Tang in:

  3. Search for Li Ling in:

  4. Search for Nan Li in:

  5. Search for Xiaoting Jia in:

  6. Search for Zhijie Zhang in:

  7. Search for Xiaorong Wang in:

  8. Search for Lejuan Shi in:

  9. Search for Jiang Yin in:

  10. Search for Ni Qiu in:

  11. Search for Hao Liu in:

  12. Search for Ying Song in:

  13. Search for Kai Luo in:

  14. Search for Hongsheng Li in:

  15. Search for Zhimin He in:

  16. Search for Guopei Zheng in:

  17. Search for Xiaoming Xie in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Guopei Zheng or Xiaoming Xie.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41388-018-0396-8