Abstract

Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α–p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

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Acknowledgements

We thank S. Kopetz for providing cetuximab and J. Chen for providing SFB-tagged expression vector. We thank D. Aten for assistance with figure presentation. This work was supported by the NIH R00 award (R00DK094981), UT Startup and UT STARS grants to C.Lin, and the NIH R00 award (R00CA166527), CPRIT award (R1218), UT Startup and UT STARS grants to L.Y.

Author information

Author notes

    • Aifu Lin
    • , Chunlai Li
    •  & Zhen Xing

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA

    • Aifu Lin
    • , Chunlai Li
    • , Zhen Xing
    • , Qingsong Hu
    • , Ke Liang
    • , Shouyu Wang
    • , Yanyan Zhang
    • , Yongkun Wei
    • , Peter K. Park
    • , Mien-Chie Hung
    • , Chunru Lin
    •  & Liuqing Yang
  2. Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, Texas 77030, USA

    • Leng Han
  3. Department of Epidemiology and Biostatistics and Ministry of Education (MOE), School of Public Health, Nanjing Medical University, 210029, China

    • Cheng Wang
    •  & Zhibin Hu
  4. Department of System Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA

    • David H. Hawke
    •  & Han Liang
  5. Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA

    • Guolin Ma
    •  & Yubin Zhou
  6. Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China

    • Jianwei Zhou
  7. Department of Oncology, Yixing People’s Hospital, 75 Zhenguan Road, Yixing 214200, China

    • Yan Zhou
  8. Department of Surgery, Division of Surgical Science, Duke University, School of Medicine, Durham, North Carolina 27710, USA

    • Jeffery R. Marks
  9. Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA

    • Han Liang
  10. The Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA

    • Mien-Chie Hung
    • , Chunru Lin
    •  & Liuqing Yang
  11. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

    • Mien-Chie Hung
  12. Center for RNA Interference and Non-Coding RNAs, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA

    • Liuqing Yang

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Contributions

C.Lin, L.Y. and A.L. designed the research, and A.L., C.Li and Z.X. performed most of the experiments, with participation of K.L., S.W., Q.H., Y.Zhang, G.M. and Yubin Z. D.H.H. executed mass spectrometry analysis. Clinical specimens were ascertained and processed by S.W., J.Z., Yan Z. and J.R.M. The histological staining and corresponding analysis were performed by K.L. and Y.W. P.K.P. helped with manuscript preparation. TCGA data and microarray data analysis was performed by C.W., Z.H., L.H. and H.L. M.-C.H. provided reagents and conceptual advice L.Y., C.Lin and A.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chunru Lin or Liuqing Yang.

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https://doi.org/10.1038/ncb3295

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