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Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

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.
Figure 2: HOTAIR promotes invasion of breast carcinoma cells.
Figure 3: HOTAIR promotes selective re-targeting of PRC2 and H3K27me3 genome-wide.
Figure 4: HOTAIR -induced matrix invasion and global gene expression changes requires PRC2.

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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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Correspondence to Howard Y. Chang.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Tables S1- S5 and Supplementary Figures S1- S10 with legends. (PDF 5579 kb)

Supplementary Table 6

The file contains the taqman real-time PCR assays employed in this study. (XLS 27 kb)

Supplementary Table 7

This file contains a list of 854 genes with HOTAIR-dependent gain of PRC2 occupancy and H3K27me3. (XLS 357 kb)

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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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