Targeted Disruption of Hotair Leads to Homeotic Transformation and Gene Derepression

Li, Lingjie; Liu, Bo; Wapinski, Orly L.; Tsai, Ming Ying; Qu, Kun; Zhang, Jiajing; Carlson, Jeff C.; Lin, Meihong; Fang, Fengqin; Gupta, Rajnish A.; Helms, Jill A.; Chang, Howard Y.

doi:10.1016/j.celrep.2013.09.003

Cited by 294 publications

(320 citation statements)

References 41 publications

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“…HOTAIR interacts with PRC2, which increases the level of H3K27me3, and subsequently decreases the expression of various genes, particularly metastasis-suppressing genes (36,37). Furthermore, the present study investigated the association between HOTAIR and PDCD4.…”

Section: A B Cmentioning

confidence: 91%

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Chen¹,

Bian²,

Zhao³

et al. 2016

Oncology Letters

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Abstract. Programmed cell death protein 4 (PDCD4) has recently been demonstrated to be implicated in translation and transcription, and the regulation of cell growth. However, the mechanisms underlying PDCD4 function in glioma cells remain to be elucidated. The current study investigated the function and regulation of PDCD4 and the results demonstrated that the expression of PDCD4 was significantly reduced in glioma cells compared with normal cells. When PDCD4 was overexpressed in glioma cells, the proliferation rate and invasive capability of the cells greatly decreased, suggesting that PDCD4 functions as a tumor suppressor in this cell type. In addition, the histone modification status of the PDCD4 gene was analyzed, and chromatin immunoprecipitation assay identified a high density of histone 3 lysine 27 trimethylation on the promoter of PDCD4, which was associated with the long non-coding RNA, homeobox transcript antisense RNA (HOTAIR). The expression of HOTAIR was significantly increased in glioma cells compared with normal cells, and it exerted its function in a polycomb repressive complex 2-dependent manner. These results may provide novel approaches to therapeutically target PDCD4 and HOTAIR in patients with gliomas. IntroductionHuman gliomas are the most prevalent malignant neoplasms of the central nervous system, with an annual incidence of ~5/100,000 worldwide (1). Despite the use of aggressive surgery in combination with chemotherapy, biological therapy and radiotherapy, gliomas continue to be therapeutically challenging (2). For patients with glioblastoma, the relative 5-year survival rate is <5% (3). Novel therapies for the treatment of glioma are warranted; recent advances in the understanding of the molecular and biological nature of this disease may facilitate the development of successful therapeutics (4).PDCD4 protein was initially determined to be overexpressed during apoptosis, which subsequently suppresses tumorigenesis (5,6). Loss of PDCD4 expression is closely associated with the progression of a number of tumors, including glioblastomas (7), and kidney, ovarian and lung cancer (8-10). Low PDCD4 expression levels correlate with poor outcomes in patients with glioblastoma multiforme (11). The frequent loss of PDCD4 in glioblastoma multiforme is partly due to epigenetic silencing secondary to 5' cytosine-phosphate-guanine island methylation (12), in addition to overexpression of microRNA (miRNA)-21, which targets PDCD4 mRNA for degradation (13). Although several studies have examined PDCD4 in glioma, the detailed molecular mechanisms underlying the role of PDCD4 in glioma remain poorly understood.Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides, which are involved in various important events, including transcriptional, epigenetic and post-transcriptional regulation (14,15). A previous study profiled the lncRNA homeobox transcript antisense RNA (HOTAIR), and the results demonstrated that HOTAIR was closely correlated with poor prognosis, molecular ...

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Section: A B Cmentioning

confidence: 91%

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Chen¹,

Bian²,

Zhao³

et al. 2016

Oncology Letters

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“…During normal developmental patterning, HOTAIR is involved in silencing a 40-kb region of the HOXD cluster, located on a separate chromosome from HOXC (Rinn et al 2007;Li et al 2013a). More recently, this lncRNA has been shown to associate with hundreds of additional sites in the genome and to initiate broad changes in gene expression when overexpressed (Gupta et al 2010;Tsai et al 2010;Chu et al 2011).…”

Section: Introductionmentioning

confidence: 99%

An RNA matchmaker protein regulates the activity of the long noncoding RNA HOTAIR

Meredith

Balas

Sindy

et al. 2016

RNA

110

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The human long noncoding RNA (lncRNA) HOTAIR acts in trans to recruit the Polycomb repressive complex 2 (PRC2) to the HOXD gene cluster and to promote gene silencing during development. In breast cancers, overexpression of HOTAIR increases metastatic potential via the repression of many additional genes. It has remained unclear what factors determine HOTAIR-dependent PRC2 activity at specific genomic loci, particularly when high levels of HOTAIR result in aberrant gene silencing. To identify additional proteins that contribute to the specific action of HOTAIR, we performed a quantitative proteomic analysis of the HOTAIR interactome. We found that the most specific interaction was between HOTAIR and the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a member of a family of proteins involved in nascent mRNA processing and RNA matchmaking. Our data suggest that A2/B1 are key contributors to HOTAIR-mediated chromatin regulation in breast cancer cells: A2/B1 knockdown reduces HOTAIR-dependent breast cancer cell invasion and decreases PRC2 activity at the majority of HOTAIR-dependent loci. We found that the B1 isoform, which differs from A2 by 12 additional amino acids, binds with highest specificity to HOTAIR. B1 also binds chromatin and associates preferentially with RNA transcripts of HOTAIR gene targets. We furthermore demonstrate a direct RNA-RNA interaction between HOTAIR and a target transcript that is enhanced by B1 binding. Together, these results suggest a model in which B1 matches HOTAIR with transcripts of target genes on chromatin, leading to repression by PRC2.

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“…These data indicate that human-specific lncRNAs may exist that do not exert their human functions in animal models. In contrast, a Hotair-deletion in mouse was associated with malformation of spine and metacarpals and a general, non-selective derepression of genes [87]. In the latest study of 18 knockout models for approved lncRNAs, only 5 displayed apparent phenotypes [88].…”

Section: Current Research Directionsmentioning

confidence: 99%

Long non-coding RNA in health and disease

2014

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Targeted Disruption of Hotair Leads to Homeotic Transformation and Gene Derepression

Cited by 294 publications

References 41 publications

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

An RNA matchmaker protein regulates the activity of the long noncoding RNA HOTAIR

Long non-coding RNA in health and disease

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