Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis (original) (raw)

Nature volume 464, pages 1071–1076 (2010)Cite this article

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Abstract

Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome1,2,3 yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities6,7,8. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

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Figure 1: HOX lincRNAs are systematically dysregulated in breast carcinoma and have prognostic value for metastasis and survival.

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Figure 2: HOTAIR promotes invasion of breast carcinoma cells.

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Figure 3: HOTAIR promotes selective re-targeting of PRC2 and H3K27me3 genome-wide.

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Figure 4: HOTAIR -induced matrix invasion and global gene expression changes requires PRC2.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in Gene Expression Omnibus (GEO) under accession numbers GSE20435 and GSE20737.

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Acknowledgements

We thank Y. Chen-Tsai, M. Guttman, G. Sen, T. Ridky, P. Khavari, V. Band and Y. Kang for advice and reagents. Supported by National Institutes of Health (NIH), Emerald Foundation, and American Cancer Society (H.Y.C.), Dermatology Foundation (R.A.G., K.C.W. and D.J.W.), Susan Komen Foundation (M.-C.T.), NSF (T.H.), and Department of Defense BCRP (S.S.). H.Y.C. is an Early Career Scientist of the Howard Hughes Medical Institute.

Author Contributions R.A.G. measured lincRNAs in cancer samples and performed all gene transfer and knockdown experiments. R.A.G. and N.S. performed cell growth, invasion, and in vivo xenograft assays. R.A.G., K.C.W., M.-C.T. and T.H. performed ChIP-chip studies and analyses. R.A.G., J.L.R. and D.J.W. performed bioinformatic analyses. J.K. performed in vivo bioluminescence studies. H.M.H., P.A. and M.J.v.d.V. procured and analysed human tumour samples. Y.W., P.B. and B.K. designed lincRNA Taqman probes and analysed tumour RNAs by qRT–PCR. R.L. and R.B.W. performed in situ hybridization studies. R.A.G., N.S., S.S. and H.Y.C. designed the experiments and interpreted the results. R.A.G. and H.Y.C. wrote the paper.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Program in Epithelial Biology,,
    Rajnish A. Gupta, Kevin C. Wang, David J. Wong, Miao-Chih Tsai, Tiffany Hung & Howard Y. Chang
  2. Stanford Cancer Center and Transgenic Mouse Research Center,,
    Jeewon Kim
  3. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA,
    Rui Li & Robert B. West
  4. Sidney Kimmel Comprehensive Cancer Center,,
    Nilay Shah & Saraswati Sukumar
  5. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA,
    Pedram Argani
  6. Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands,
    Hugo M. Horlings & Marc J. van de Vijver
  7. The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA ,
    John L. Rinn
  8. Applied Biosystems, Foster City, California 94404, USA ,
    Yulei Wang, Pius Brzoska & Benjamin Kong

Authors

  1. Rajnish A. Gupta
  2. Nilay Shah
  3. Kevin C. Wang
  4. Jeewon Kim
  5. Hugo M. Horlings
  6. David J. Wong
  7. Miao-Chih Tsai
  8. Tiffany Hung
  9. Pedram Argani
  10. John L. Rinn
  11. Yulei Wang
  12. Pius Brzoska
  13. Benjamin Kong
  14. Rui Li
  15. Robert B. West
  16. Marc J. van de Vijver
  17. Saraswati Sukumar
  18. Howard Y. Chang

Corresponding author

Correspondence toHoward Y. Chang.

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Gupta, R., Shah, N., Wang, K. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.Nature 464, 1071–1076 (2010). https://doi.org/10.1038/nature08975

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Editorial Summary

Chromatin in cancer metastasis

Long non-coding RNAs (lincRNAs), a relatively recently recognized class of widely transcribed genes, are thought to affect chromatin state and epigenetic regulation, but their mechanisms of action and potential roles in human disease are poorly understood. This study shows that long non-coding RNAs in the human HOX loci are systematically dysregulated during breast cancer progression, and that expression levels of the lincRNA termed HOTAIR can predict cancer metastasis. Elevated levels of HOTAIR can lead to altered patterns of Polycomb binding to the genome. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.