Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

By Rajnish A. Gupta, Nilay Shah, Kevin C. Wang, Jeewon Kim, Hugo M. Horlings, D. Wong, Miao-Chih Tsai, T. Hung, P. Argani, Johannes Rinn and 8 more. Nature, 2010

5,125 citations recorded by the source corpus.

Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. 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 activities. 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bed435222ddb9e9390677ad3eef22422468512e8

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Citations in the corpus

The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. (2013, background): “For example, the ncRNA HOTAIR (Hox transcript antisense RNA) is highly expressed in breast cancer and is a predictor for metastasis formation and associated with a poor prognosis (17).”
The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “…physiological and pathological relevance of this finding awaits further investigation, but the finding that long noncoding RNAs can increase gene expression and that some such as HOTAIR promote cancer metastasis (Gupta et al. 2010) paves the way for high interest in this new regulatory mechanism.”
Tumor Metastasis: Molecular Insights and Evolving Paradigms (2011, background): “Additionally, other classes of noncoding RNAs, including large intervening noncoding RNAs (lincRNAs) such as HOTAIR (Gupta et al., 2010), have also been proposed as putative biomarkers for metastatic propensity in human breast tumors.”
Long Noncoding RNAs: Past, Present, and Future (2013, background): “Review 655 (Gupta et al. 2010), liver (Z. Yang et al. 2011), colorectal (Kogo et al. 2011), gastrointestinal (Niinuma et al. 2012), and pancreatic (Kim et al. 2012) cancers and is proposed to increase tumor invasiveness and metastasis (Gupta et al. 2010).”
Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs (2012, background): “This includes breast cancer (53), colorectal cancer (81), prostate cancer (82), hepatocellular carcinoma (83–85), leukemia (86,87), melanoma (88) and possibly others (76,89).”
The Landscape of long non-coding RNA classification (2015, neutral): “This approach has revealed many important functional lncRNAs, such as HOTAIR, which mediates gene silencing by facilitating localization of the epigenetic repressor Polycomb repressive complex 2 (PRC2) to its target sequence [72].”
Long intergenic non-coding RNAs – New links in cancer progression (2011, background): “Numerous HOX lincRNAs were found to be differently expressed between primary breast carcinomas and distant metastases (11), and many p53-dependent lincRNAs were identified in”
TANRIC: An interactive open platform to explore the function of lncRNAs in cancer (2015, neutral): “For example, elevated BCAR4 expression has been shown to significantly correlate with shorter survival time of breast cancer patients (22); and HOTAIR, a well-studied lncRNA, is known to be coexpressed with HOXC genes (23).”
Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “In human cell lines, the HOTAIR lncRNA transcribed from the HOX C cluster inhibits transcription from HOX D cluster by guiding the recruitment of histone modifiers to specific chromatin in HOX D region [39,86,87].”