HOTAIR

Gene Summary

Gene:HOTAIR; HOX transcript antisense RNA
Aliases: HOXAS, HOXC-AS4, HOXC11-AS1, NCRNA00072
Location:12q13.13
Summary:This gene is located within the Homeobox C (HOXC) gene cluster on chromosome 12 and is co-expressed with HOXC genes. It represses transcription of HOXD genes on chromosome 2 in trans. This gene is shuttled from chromosome 12 to chromosome 2 by a component of Polycomb Repressive Complex 2 (PRC2). This gene interacts with both PRC2 and lysine specific demethylase 1 (LSD1) complexes through its 5' and 3' domains, respectively, and serves as a scaffold to assemble PRC2 and LSD1 complexes to the HOXD gene cluster. It couples H3K27 methylation and H3K4 demethylation for epigenetic silencing of HOXD genes in multiple tissues. This gene is highly expressed in multiple tumors. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Feb 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 27 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HOTAIR (cancer-related)

Zhang H, Diab A, Fan H, et al.
PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis.
Cancer Res. 2015; 75(11):2363-74 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
Elucidating mechanisms of hepatitis B virus (HBV)-mediated hepatocarcinogenesis is needed to gain insights into the etiology and treatment of liver cancer. Cells where HBV is replicating exhibit increased expression of Plk1 kinase and reduced levels of two transcription repression factors, SUZ12 and ZNF198. SUZ12 is an essential subunit of the transcription repressive complex PRC2. ZNF198 stabilizes the transcription repressive complex composed of LSD1, Co-REST, and HDAC1. These two transcription repressive complexes are held together by binding the long noncoding RNA HOTAIR. In this study, we linked these regulatory events mechanistically by showing that Plk1 induces proteasomal degradation of SUZ12 and ZNF198 by site-specific phosphorylation. Plk1-dependent ubiquitination of SUZ12 and ZNF198 was enhanced by expression of HOTAIR, significantly reducing SUZ12 and ZNF198 stability. In cells expressing the HBV X protein (HBx), downregulation of SUZ12 and ZNF198 mediated global changes in histone modifications. In turn, HBx-expressing cells propagated an altered chromatin landscape after cell division, as exemplified by changes in histone modifications of the EpCAM promoter, a target of PRC2 and LSD1/Co-REST/HDAC1 complexes. Notably, liver tumors from X/c-myc bitransgenic mice exhibited downregulation of SUZ12 and ZNF198 along with elevated expression of Plk1, HOTAIR, and EpCAM. Clinically, similar effects were documented in a set of HBV-related liver tumors consistent with the likelihood that downregulation of SUZ12 and ZNF198 leads to epigenetic reprogramming of infected hepatocytes. Because both Plk1 and HOTAIR are elevated in many human cancers, we propose that their combined effects are involved in epigenetic reprogramming associated broadly with oncogenic transformation.

Yamamoto S, Han W, Kim Y, et al.
Breast Cancer: Radiogenomic Biomarker Reveals Associations among Dynamic Contrast-enhanced MR Imaging, Long Noncoding RNA, and Metastasis.
Radiology. 2015; 275(2):384-92 [PubMed] Related Publications
PURPOSE: To perform a radiogenomic analysis of women with breast cancer to study the multiscale relationships among quantitative computer vision-extracted dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging phenotypes, early metastasis, and long noncoding RNA (lncRNA) expression determined by means of high-resolution next-generation RNA sequencing.
MATERIALS AND METHODS: In this institutional review board-approved study, an automated image analysis platform extracted 47 computational quantitative features from DCE MR imaging data in a training set (n = 19) to screen for MR imaging biomarkers indicative of poor metastasis-free survival (MFS). The lncRNA molecular landscape of the candidate feature was defined by using an RNA sequencing-specific negative binomial distribution differential expression analysis. Then, this radiogenomic biomarker was applied prospectively to a validation set (n = 42) to allow prediction of MFS and lncRNA expression by using quantitative polymerase chain reaction analysis.
RESULTS: The quantitative MR imaging feature, enhancing rim fraction score, was predictive of MFS in the training set (P = .007). RNA sequencing analysis yielded an average of 55.7 × 10(6) reads per sample and identified 14 880 lncRNAs from a background of 189 883 transcripts per sample. Radiogenomic analysis allowed identification of three previously uncharacterized and five named lncRNAs significantly associated with high enhancing rim fraction, including Homeobox transcript antisense intergenic RNA (HOTAIR) (P < .05), a known predictor of poor MFS in patients with breast cancer. Independent validation confirmed the association of the enhancing rim fraction phenotype with both MFS (P = .002) and expression of four of the top five differentially expressed lncRNAs (P < .05), including HOTAIR.
CONCLUSION: The enhancing rim fraction score, a quantitative DCE MR imaging lncRNA radiogenomic biomarker, is associated with early metastasis and expression of the known predictor of metastatic progression, HOTAIR.

Wang J, Song YX, Wang ZN
Non-coding RNAs in gastric cancer.
Gene. 2015; 560(1):1-8 [PubMed] Related Publications
Non-coding RNAs (ncRNAs) have recently become increasingly important in the study of cellular metabolism and regulation such as development, proliferation, differentiation and apoptosis. However, the functions of most ncRNAs have remained largely unknown. Recently, studies have begun to characterize the aberrant regulation of ncRNAs in gastric cancer (GC) cells and tissues. These ncRNAs have a close relationship with drug resistance, and with the occurrence, development, invasion and metastasis of tumors, so they could possibly become new therapeutic targets and treatment tools for GC in the future. The present review summarized current advances in our knowledge of the roles of ncRNAs in GC.

Bayram S, Sümbül AT, Batmacı CY, Genç A
Effect of HOTAIR rs920778 polymorphism on breast cancer susceptibility and clinicopathologic features in a Turkish population.
Tumour Biol. 2015; 36(5):3863-70 [PubMed] Related Publications
Overexpression of Hox transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA (lncRNA), is associated with cancer cell proliferation, invasion, progression, and metastasis as well as poor survival in a variety of human cancers including breast cancer (BC). A common functional single nucleotide polymorphism (SNP) rs920778 (T → C) in the intronic enhancer of the HOTAIR has been reported to influence HOTAIR expression and cancer predisposition, but the association of HOTAIR rs920778 polymorphism with BC susceptibility and clinicopathological features has yet to be investigated. We genotyped HOTAIR rs920778 polymorphism in 245 Turkish women including 123 BC patients and 122 age-matched healthy controls by a real-time polymerase chain reaction (PCR) with the TaqMan assay. We found that the CC genotype of HOTAIR rs920778 polymorphism significantly increased the risk of BC in both codominant (odds ratio (OR) = 2.12, 95 % confidence interval (CI) 1.00-4.51, P = 0.05) and recessive (OR = 2.40, 95 % CI 1.22-4.73, P = 0.01) inheritance genetic models. Our research also indicated an association between the CC genotype of HOTAIR rs920778 polymorphism and clinicopathologic features of tumor, including advanced tumor-node-metastasis (TNM) stage, larger tumor size, distant metastasis, and poor histological grade (P < 0.05). Because our findings suggest for the first time that the CC genotype of HOTAIR rs920778 polymorphism might play important roles in genetic susceptibility to BC development and aggressiveness in a Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different populations.

Jing L, Yuan W, Ruofan D, et al.
HOTAIR enhanced aggressive biological behaviors and induced radio-resistance via inhibiting p21 in cervical cancer.
Tumour Biol. 2015; 36(5):3611-9 [PubMed] Related Publications
We previously reported the frequent overexpression of HOX Antisense Intergenic RNA (HOTAIR) in human cervical cancer, which was significantly correlated with tumor progression and poor prognosis. In the present study, we investigated the detailed biological functions of HOTAIR in cervical cancer. In vitro, upregulation of HOTAIR inhibited apoptosis and promoted cellular proliferation, cell cycle progression, migration, and invasion; on the contrast, downregulation of HOTAIR induced more apoptosis, suppressed cellular proliferation, cell cycle, migration, and invasion. Moreover, a high level of HOTAIR was notably associated with radio-resistance and downregulation of p21 in the primary cultured cervical cancer cells. Further, we demonstrated that elevated HOTAIR could induce radio-resistance via inhibiting p21 in HeLa cells, while knockdown of HOTAIR upregulated p21 and consequentially increased the radio-sensitivity of C33A cells. Consistently, stable knockdown of HOTAIR significantly suppressed tumor growth and sensitized cervical cancer to radiotherapy in vivo. In conclusion, HOTAIR served as an onco-lncRNA in cervical cancer which could enhance various aggressive biological behaviors. Moreover, we proved that HOTAIR execute its functions mainly through inhibiting the p21 expression. These results proposed that targeting HOTAIR might be a potent therapeutic strategy in cervical cancer, especially for those patients who accepted radiotherapy.

Gan L, Xu M, Zhang Y, et al.
Focusing on long noncoding RNA dysregulation in gastric cancer.
Tumour Biol. 2015; 36(1):129-41 [PubMed] Related Publications
As the discovery of functions of long noncoding RNA (lncRNA) HOTAIR lifts ncRNA to new levels, large numbers of research have been demonstrated for the roles of lncRNAs in diverse biological processes, such as development, cellular differentiation, and a wide range of diseases including cancer. And, recent studies have discovered that lncRNAs can participate in almost every step in the life cycle of gene regulation, including chromosome dosage compensation, imprinting, epigenetic regulation, nuclear and cytoplasmic trafficking, transcription, mRNA splicing, and translation, mainly in the four archetypes-signals, decoys, guides, and scaffolds. Unsurprisingly, accumulating studies have demonstrated that serious lncRNAs are dysregulated in gastric cancer (GC), one of the major causes of cancer-related mortality worldwide, and closely related to tumorigenesis, metastasis, or prognosis. In this review, we will discuss diverse functions of lncRNAs and highlight the growing evidence for the important roles of lncRNAs acting as biomarkers for the early diagnosis of GC, as indicators of GC prognosis, or even as therapeutic targets in GC.

Guo W, Dong Z, Bai Y, et al.
Associations between polymorphisms of HOTAIR and risk of gastric cardia adenocarcinoma in a population of north China.
Tumour Biol. 2015; 36(4):2845-54 [PubMed] Related Publications
As an important long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR) is involved in the development and progression of various carcinomas. However, the role and genetic alterations of HOTAIR in gastric cardia adenocarcinoma (GCA) occurrence and progression have not been elucidated. We performed a case-control study in a population of north China to evaluate the possible association between haplotype-tagging SNPs (htSNPs) of the whole HOTAIR sequence and the risk of GCA as well as functional effect of the susceptibility single nucleotide polymorphism (SNP) rs12826786 on gene expression. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to examine the genotype of htSNPs in 515 GCA patients and 654 control subjects, and the quantitative real-time reverse transcription PCR (RT-PCR) method was used to examine the expression of HOTAIR in 102 GCA patients. A family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing GCA. Among three htSNPs of the HOTAIR gene (rs12826786 C>T, rs4759314 A>G, and rs10783618 C>T), only the T allele of rs12826786 was found to increase the risk of developing GCA and was associated with smoking habit and tumor-node-metastasis (TNM) stage. In addition, higher expression levels of HOTAIR were found in tumor tissues and rs12826786 SNP has a genotype-specific effect on HOTAIR expression. A high HOTAIR expression level was associated with poor GCA patients' survival. These results indicate that functional genotype alteration of rs12826786 SNP may influence the expression of HOTAIR, and HOTAIR may be a useful marker to predict the biological behavior of tumors and potentially a therapeutic target in GCA treatment.

Xue Y, Ma G, Gu D, et al.
Genome-wide analysis of long noncoding RNA signature in human colorectal cancer.
Gene. 2015; 556(2):227-34 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been widely regarded as crucial regulators in various biological processes involved in carcinogenesis. However, the comprehensive lncRNA expression signature in colorectal cancer remains fully unknown. We performed a high throughput microarray assay to detect lncRNA expression profile in three paired human colorectal cancer tissues and their adjacent normal tissues. Additional 90 paired colorectal samples were collected to verify differently expression levels of two selected lncRNAs using q-RT-PCR assay. Bioinformatic approaches were performed to explore into the functions of these differently expressed lncRNAs. Microarray assay showed a series of lncRNAs were differently expressed in colorectal cancer. Two of the lncRNAs, HOTAIR and a novel lncRNA, lncRNA-422 were confirmed in more samples (P=0.015 for HOTAIR and P=0.027 for lncRNA-422, respectively). GSEA indicated that gene sets most correlated with them were those named up-regulated in KRAS-over, down-regulated in JAK2-knockout, down-regulated in PDGF-over and down-regulated in TBK1-knockout, all of which were cancer-related. Subsequently, GO analyses of most significantly correlated coding genes of HOTAIR and lncRNA-422 showed that these two lncRNAs may participate in carcinogenesis by regulating protein coding genes involved in special biological process relevant to cancer. Our study demonstrated that different lncRNA expression patterns were involved in colorectal cancer. Besides, HOTAIR and lncRNA-422 were identified to participate in colorectal cancer. Further studies into biological mechanisms of differently expressed lncRNAs identified in our study will help to provide new perspective in colorectal cancer pathogenesis.

Liu Y, Luo F, Xu Y, et al.
Epithelial-mesenchymal transition and cancer stem cells, mediated by a long non-coding RNA, HOTAIR, are involved in cell malignant transformation induced by cigarette smoke extract.
Toxicol Appl Pharmacol. 2015; 282(1):9-19 [PubMed] Related Publications
The incidence of lung diseases, including cancer, caused by cigarette smoke is increasing, but the molecular mechanisms of gene regulation induced by cigarette smoke remain unclear. This report describes a long noncoding RNA (lncRNA) that is induced by cigarette smoke extract (CSE) and experiments utilizing lncRNAs to integrate inflammation with the epithelial-mesenchymal transition (EMT) in human bronchial epithelial (HBE) cells. The present study shows that, induced by CSE, IL-6, a pro-inflammatory cytokine, leads to activation of STAT3, a transcription activator. A ChIP assay determined that the interaction of STAT3 with the promoter regions of HOX transcript antisense RNA (HOTAIR) increased levels of HOTAIR. Blocking of IL-6 with anti-IL-6 antibody, decreasing STAT3, and inhibiting STAT3 activation reduced HOTAIR expression. Moreover, for HBE cells cultured in the presence of HOTAIR siRNA for 24h, the CSE-induced EMT, formation of cancer stem cells (CSCs), and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates HOTAIR in an autocrine manner, contributes to the EMT and to CSCs induced by CSE. These data define a link between inflammation and EMT, processes involved in the malignant transformation of cells caused by CSE. This link, mediated through lncRNAs, establishes a mechanism for CSE-induced lung carcinogenesis.

Kim HJ, Lee DW, Yim GW, et al.
Long non-coding RNA HOTAIR is associated with human cervical cancer progression.
Int J Oncol. 2015; 46(2):521-30 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
The functions of many long non-coding RNAs (lncRNAs) in human cancers remain to be clarified. The lncRNA Hox transcript antisense intergenic RNA (HOTAIR) has been reported to reprogram chromatin organization and promote breast and colorectal cancer metastasis, the involvement of lncRNAs in cervical cancer is just beginning to be studied. In the present study, we examined the expression and the functional role of HOTAIR in cervical cancer. HOTAIR expression was determined in cervical cancer tissues (n=111) and corresponding normal tissues (n=40) by using real-time polymerase chain reaction, and its correlation with clinical parameters and prognosis were analyzed. To determine the effect of HOTAIR knockdown and overexpression in cervical cancer cell lines, we used the CCK-8 assay, wound healing migration and matrigel invasion assay. The expression level of HOTAIR in cervical cancer tissues was higher than that in corresponding non-cancerous tissues. High HOTAIR expression correlated with lymph node metastasis, and reduced overall survival. A multivariate analysis showed that HOTAIR was a prognostic factor for predicting cervical cancer recurrence. Knockdown of HOTAIR reduced cell proliferation, migration, and invasion in cervical cancer cell lines. Moreover, HOTAIR regulated the expression of vascular endothelial growth factor, matrix metalloproteinase-9 and epithelial-to-mesenchymal transition (EMT)-related genes, which are important for cell motility and metastasis. Therefore, HOTAIR may promote tumor aggressiveness through the upregulation of VEGF and MMP-9 and EMT-related genes. These findings indicate that HOTAIR may represent a novel biomarker for predicting recurrence and prognosis and serve as a promising therapeutic target in cervical cancer.

Zhou X, Chen J, Tang W
The molecular mechanism of HOTAIR in tumorigenesis, metastasis, and drug resistance.
Acta Biochim Biophys Sin (Shanghai). 2014; 46(12):1011-5 [PubMed] Related Publications
Long non-coding RNAs have been reported to play an important role in cellular metabolism and development. Homeobox transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA, is pervasively over-expressed in most human cancers compared with non-cancerous adjacent tissues. Although many articles have reported that HOTAIR is closely associated with metastasis, epithelial-mesenchymal transition, advanced pathological stage, drug resistance, and poor prognosis, the role of HOTAIR in gene regulation and tumor development is largely unknown, and the potential molecular mechanisms are not completely clear yet. In this review, we summarized the recent progress in the study of the major functions of HOTAIR. miR-331-3p, miR-130a, miR-7, miR-141, HER2, c-MYC, WIF-1, RBM38, PTEN, and Col-1 are involved in the HOTAIR regulation network. We tried to elucidate the molecular mechanisms of HOTAIR in the aspects of tumorigenesis, metastasis, drug resistance, and regulation.

Xu Y, Wang J, Qiu M, et al.
Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma.
Tumour Biol. 2015; 36(3):1643-51 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide, especially in Eastern Asia. The prognosis of ESCC remains poor; thus, it is still necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recent studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Some lncRNAs, such as HOTAIR and POU3F3, were reported to play important roles in ESCC. Here, we characterized the expression profile of taurine-upregulated gene 1 (TUG1), a lncRNA recruiting and binding to polycomb repressive complex 2 (PRC2), in ESCC. In a cohort of 62 patients, TUG1 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues, and high expression level of TUG1 was associated with family history and upper segment of esophageal cancer (p < 0.05). Further, in vitro silencing TUG1 via siRNA inhibited the proliferation and migration of ESCC cells and blocked the progression of cell cycle. Therefore, our study indicates that TUG1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.

Yao Y, Li J, Wang L
Large intervening non-coding RNA HOTAIR is an indicator of poor prognosis and a therapeutic target in human cancers.
Int J Mol Sci. 2014; 15(10):18985-99 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
In the human genome, the fraction of protein-coding genes that are stably transcribed is only up to 2%, with the remaining numerous RNAs having no protein-coding function. These non-coding RNAs (ncRNAs) have received considerable attention in cancer research in recent years. Breakthroughs have been made in understanding microRNAs and small interfering RNAs, but larger RNAs such as long ncRNAs (lncRNAs) remain an enigma. One lncRNA, HOX antisense intergenic RNA (HOTAIR), has been shown to be dysregulated in many types of cancer, including breast cancer, colorectal cancer, and hepatoma. HOTAIR functions as a regulatory molecule in a wide variety of biological processes. However, its mechanism of action has not been clearly elucidated. It is widely believed that HOTAIR mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Further study of HOTAIR-related pathways and the role of HOTAIR in tumorigenesis and tumor progression may identify new treatment targets. In this review, we will focus on the characteristics of HOTAIR, as well as data pertaining to its mechanism and its association with cancers.

Li JT, Wang LF, Zhao YL, et al.
Nuclear factor of activated T cells 5 maintained by Hotair suppression of miR-568 upregulates S100 calcium binding protein A4 to promote breast cancer metastasis.
Breast Cancer Res. 2014; 16(5):454 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
INTRODUCTION: The onset of distal metastasis, which underlies the high mortality of breast cancers, warrants substantial studies to depict its molecular basis. Nuclear factor of activated T cells 5 (NFAT5) is upregulated in various malignancies and is critically involved in migration and invasion of neoplastic cells. Nevertheless, the metastasis-related events potentiated by this transcriptional factor and the mechanism responsible for NFAT5 elevation in carcinoma cells remain to be fully elucidated.
METHODS: The correlation of NFAT5 with breast cancer invasiveness was investigated in vitro and clinically. The genes transcriptionally activated by NFAT5 were probed and their roles in breast cancer progression were dissected. The upstream regulators of NFAT5 were studied with particular attempt to explore the involvement of non-coding RNAs, and the mechanism underlying the maintenance of NFAT5 expression was deciphered.
RESULTS: In metastatic breast cancers, NFAT5 promotes epithelial-mesenchymal transition (EMT) and invasion of cells by switching on the expression of the calcium binding protein S100A4, and facilitates the angiogenesis of breast epithelial cells and thus the development of metastases by transcriptionally activating vascular endothelial growth factor C (VEGF-C). NFAT5 is directly targeted by miR-568, which is in turn suppressed by the long non-coding RNA, Hotair, via a documented in trans gene silencing pattern, that is recruitment of the polycomb complex (Polycomb Repressive Complex 2; PRC2) and LSD1, and consequently methylation of histone H3K27 and demethylation of H3K4 on the miR-568 loci.
CONCLUSION: This study unravels a detailed role of NFAT5 in mediating metastatic signaling, and provides broad insights into the involvement of Hotair, in particular, by transcriptionally regulating the expression of microRNA(s), in the metastasis of breast cancers.

Su X, Malouf GG, Chen Y, et al.
Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes.
Oncotarget. 2014; 5(20):9864-76 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.

Malek E, Jagannathan S, Driscoll JJ
Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer.
Oncotarget. 2014; 5(18):8027-38 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
The therapeutic response and clinical outcome of patients diagnosed with the same cancer type and that receive identical treatment is highly variable to reflect the genetic heterogeneity within tumor cells. Non-coding RNAs (ncRNAs) are recently discovered molecules that regulate eukaryotic gene expression and represent a significant advance towards a better understanding of the mechanisms that govern cellular growth. NcRNAs are essential for the proper regulation of cell proliferation and survival under physiologic conditions and are deregulated in many pathologies, e.g., human cancers. NcRNAs have been associated with cancer diagnosis, staging, treatment response, metastasis and survival and include distinct subtypes, e.g., long ncRNAs (lncRNAs) and microRNAs (miRNAs). LncRNAs have been linked to essential growth-promoting activities and their deregulation contributes to tumor cell survival. A prominent example is the Hox transcript antisense intergenic lncRNA, HOTAIR, that cooperates with the polycomb repressive complex to reprogram chromatin organization. HOTAIR expression is deregulated in a spectrum of cancers and HOTAIR expression correlates with patient survival. Here, we highlight emerging evidence that supports a role for lncRNAs in cancer with implications for the development of novel diagnostics and therapeutics.

Wu Y, Zhang L, Wang Y, et al.
Long noncoding RNA HOTAIR involvement in cancer.
Tumour Biol. 2014; 35(10):9531-8 [PubMed] Related Publications
Evidences have been provided that long noncoding RNAs (lncRNAs) act as key molecules in epigenetic regulation and are involved in the development process of cancer in recent studies. HOX transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), functions as a molecular scaffold to link and target two histone modification complexes PRC2 and LSD1, then reprograms chromatin states by couples histone H3K27 methylation and H3K4 demethylation for epigenetic gene silencing to promote cancer metastasis. HOTAIR, regarded as an oncogene, is pervasively overexpressed in most solid cancers and correlated with tumor invasion, progression, metastasis, and poor prognosis, and HOTAIR has been proven to play a critical role in most biological process of cancer and would be a potential new target in cancer therapy.

Zhang S, Chen S, Yang G, et al.
Long noncoding RNA HOTAIR as an independent prognostic marker in cancer: a meta-analysis.
PLoS One. 2014; 9(8):e105538 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
BACKGROUND: HOTAIR, a newly discovered long intergenic noncoding RNA (lincRNA), has been reported to be aberrantly expressed in many types of cancers. This meta-analysis summarizes its potential role as a biomarker in malignancy.
METHODS: A quantitative meta-analysis was performed through a systematic search in Pubmed, Medline and Web of Science for eligible papers on the prognostic impact of HOTAIR in cancer from inception to Feb. 28, 2014. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to summarize the effect.
RESULTS: Nineteen studies were included in the study, with a total of 2033 patients. A significant association was observed between high HOTAIR expression and poor overall survival (OS) in patients with cancer (pooled HR 2.22, 95% CI: 1.68-2.93). Place of residence (Asian or Western countries), type of cancer (digestive or non-digestive disease), sample size (more or less than 100), and paper quality (score more or less than 85%) did not alter the significant predictive value of HOTAIR in OS from various kinds of cancer but preoperative status did. By combining HRs from Cox multivariate analyses, we found that HOTAIR expression was an independent prognostic factor for cancer patients (pooled HR 2.26, 95% CI: 1.62-3.15). Subgroup analysis showed that HOTAIR abundance was an independent prognostic factor for cancer metastasis (HR 3.90, 95% CI: 2.25-6.74). For esophageal carcinoma, high HOTAIR expression was significantly associated with TNM stage (III/IV vs. I/II: OR 6.90, 95% CI: 2.81-16.9) without heterogeneity. In gastric cancer, HOTAIR expression was found to be significantly associated with lymph node metastases (present vs. absent: OR 4.47, 95% CI: 1.88-10.63) and vessel invasion (positive vs. negative: OR 2.88, 95% CI: 1.38-6.04) without obvious heterogeneity.
CONCLUSIONS: HOTAIR abundance may serve as a novel predictive factor for poor prognosis in different types of cancers in both Asian and Western countries.

Wu Y, Liu J, Zheng Y, et al.
Suppressed expression of long non-coding RNA HOTAIR inhibits proliferation and tumourigenicity of renal carcinoma cells.
Tumour Biol. 2014; 35(12):11887-94 [PubMed] Related Publications
Although long non-coding RNAs (lncRNAs) are known to play an important role in cell regulation in several cancers, the regulatory mechanisms in renal carcinoma cells remain unclear. HOX transcript antisense RNA (HOTAIR), an lncRNA, coordinates with chromatin-modifying enzymes to regulate gene silencing. HOTAIR is over-expressed in several types of carcinoma cells. Thus, we hypothesised that lncRNA HOTAIR is crucial for cell proliferation and invasion and that its knockdown induces apoptosis in renal carcinoma cells. lncRNA HOTAIR expression was found to be elevated in renal carcinoma cells. Additionally, lncRNA HOTAIR knockdown by RNA interference with siRNA was found to significantly affect the cell cycle in the G0/G1 phase and weaken the abilities of cell proliferation and invasion in vitro. Xenograft experiments confirmed that the growth of xenograft tumours formed by renal carcinoma cells was suppressed after silencing lncRNA HOTAIR expression. Moreover, chromatin immunoprecipitation (ChIP) and RNA-binding protein immunoprecipitation (RIP) assays revealed that knockdown of lncRNA HOTAIR led to the weakening of the recruitment and binding abilities of EZH2 and H3K27me3 locus with lncRNA HOTAIR. Furthermore, the cell cycle-related gene locus was in an active transcriptional state by the silencing of lncRNA HOTAIR expression and modulation of covalent histones.

Chakravadhanula M, Ozols VV, Hampton CN, et al.
Expression of the HOX genes and HOTAIR in atypical teratoid rhabdoid tumors and other pediatric brain tumors.
Cancer Genet. 2014; 207(9):425-8 [PubMed] Related Publications
Pediatric brain tumors such as atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive and predominantly occur in young children. A characteristic feature of ATRT is aberrations of the SMARCB1 (hSNF5/INI1) gene. Developmental gene defects may play an important role in the biology of pediatric brain tumors. HOX genes are transcription factors that play a pivotal role in anterior-posterior body axis patterning and are misexpressed in tumors such as lung carcinoma, neuroblastoma, and glioma. HOX genes are also known to be associated with long noncoding RNAs (lncRNAs) such as HOTAIR, which induces transcriptional silencing of the HOXD locus by recruiting polycomb repressive complex 2 to the HOXD locus. In this study, transcriptome analysis using the nanoString platform was performed, and expression of the HOX and HOTAIR genes was studied in pediatric tumors: 20 ATRTs, 10 ependymomas, 10 medulloblastomas, six glioblastoma multiforme, and nine juvenile pilocytic astrocytomas (JPAs). Results indicate that in ATRTs, medulloblastomas, and JPAs, the HOTAIR and HOXC genes are highly expressed; however, HOXD8-10 genes are not silenced. In ependymomas, there is low expression of the HOXC, HOTAIR, and HOXD8-10 genes. These interesting results need to be elucidated further so that the functions of these genes in pediatric tumors is understood.

Lee NK, Lee JH, Park CH, et al.
Long non-coding RNA HOTAIR promotes carcinogenesis and invasion of gastric adenocarcinoma.
Biochem Biophys Res Commun. 2014; 451(2):171-8 [PubMed] Related Publications
Gastric cancer is one of the major causes of cancer death worldwide; however, the mechanism of carcinogenesis is complex and poorly understood. Long non-coding RNA HOTAIR (HOX transcript antisense RNA) recently emerged as a promoter of metastasis in various cancers including gastric cancer. Here we investigated the impact of HOTAIR on apoptosis, cell proliferation and cell cycle to dissect the carcinogenesis of gastric cancer. We examined the mechanism of invasion and metastasis and analyzed the clinical significance of HOTAIR. Downregulation of HOTAIR was confirmed by two different siRNAs. The expression of HOTAIR was significantly elevated in various gastric cancer cell lines and tissues compared to normal control. si-HOTAIR significantly reduced viability in MKN 28, MKN 74, and KATO III cells but not in AGS cells. si-HOTAIR induced apoptosis in KATO III cells. Lymphovascular invasion and lymph node metastasis were more common in the high level of HOTAIR group. si-HOTAIR significantly decreased invasiveness and migration. si-HOTAIR led to differential expression of epithelial to mesenchymal transition markers. We found that HOTAIR was involved in inhibition of apoptosis and promoted invasiveness, supporting a role for HOTAIR in carcinogenesis and progression of gastric cancer.

Yan TH, Lu SW, Huang YQ, et al.
Upregulation of the long noncoding RNA HOTAIR predicts recurrence in stage Ta/T1 bladder cancer.
Tumour Biol. 2014; 35(10):10249-57 [PubMed] Related Publications
Stage Ta/T1 urothelial carcinoma of the bladder (Ta/T1 BC) has a marked tendency to recurrence. Long noncoding RNA HOTAIR has been reported to be expressed in some human cancers such as breast cancer, and it may be positively correlated with patient's prognosis. The aim of our study was to evaluate the prognostic value of HOTAIR in Ta/T1 BC. HOTAIR expression in Ta/T1 BC tissues and adjacent normal tissues was collected from 110 patients and measured by real-time quantitative PCR. The relationships between HOTAIR and the clinical pathological characteristics of Ta/T1 BC patients were analyzed. Immunohistochemistry was done to detect the protein of Wnt inhibitory factor 1 (WIF-1) as well. Ninety out of 110 specimens were detected in HOTAIR high expression. Histological grade and expression levels of HOTAIR were positively correlated with the recurrence rate. HOTAIR expression (hazard ratio 4.712; 95 % CI 2.894-8.714; P < 0.001) was an independent predictor of recurrence rate in multivariate Cox regression analysis. HOTAIR expression is correlated with patients' poor prognosis. A significant inverse correlation between HOTAIR and WIF-1 expression was demonstrated in Ta/T1 BC tissues. The expression levels of HOTAIR are an independent prognostic factor of recurrence in Ta/T1 BC patients.

Cai B, Song XQ, Cai JP, Zhang S
HOTAIR: a cancer-related long non-coding RNA.
Neoplasma. 2014; 61(4):379-91 [PubMed] Related Publications
Long non-coding RNA was dismissed as merely transcriptional "noise" in the past decades. Numerous researches have shown that lncRNAs regulated gene expression at the epigenetic level. Moreover, lncRNAs played important roles in proliferation, apoptosis and invasiveness of tumor cells, and participated in metastatic capacity of cancers. Recent studies revealed HOX transcript antisense RNA, a lncRNA with regulatory functions of transcription, could bind PRC2 and LSD1/CoREST/REST complexes and direct to the specific gene sites, resulted in H3K27 methylation and H3K4 demethylation and ultimately gene silencing. Aberrant HOTAIR expression was associated with various sites of cancers such as breast, hepatocellular, gastric, colorectal, pancreatic et al; and affected survival and prognosis of cancer patients. In this review, we introduce an overall view of HOTAIR by describing the known molecular mechanisms and potential functions of HOTAIR and summarizing the latest progresses on the research of HOTAIR in various human cancers.

Cai B, Wu Z, Liao K, Zhang S
Long noncoding RNA HOTAIR can serve as a common molecular marker for lymph node metastasis: a meta-analysis.
Tumour Biol. 2014; 35(9):8445-50 [PubMed] Related Publications
A number of studies have reported that HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and overexpression of HOTAIR was prone to lymph node metastasis. This meta-analysis collected all relevant articles and explored the association between HOTAIR expression levels with lymph node metastasis. A literature collection was conducted by searching electronic databases PubMed, Cochrane Library, OVID, Web of Science, and CNKI (up to March 22, 2014). The odds ratio (OR) and its corresponding 95 % confidence interval (CI) were calculated to assess the strength of the association by using RevMan5.2 software. A total of 748 patients from 8 studies were included in this meta-analysis. The results showed there was a significant difference in the incidence of lymph node metastasis between high HOTAIR expression group and low HOTAIR expression group (OR = 2.81, 95 % CI 1.38-5.70, P = 0.004 random-effects model). This meta-analysis demonstrated that the incidence of lymph node metastasis in patients detected with high HOTAIR expression was higher than that in patients with low HOTAIR expression.

Ma MZ, Li CX, Zhang Y, et al.
Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer.
Mol Cancer. 2014; 13:156 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
BACKGROUND: Protein coding genes account for only about 2% of the human genome, whereas the vast majority of transcripts are non-coding RNAs including long non-coding RNAs. A growing volume of literature has proposed that lncRNAs are important players in cancer. HOTAIR was previously shown to be an oncogene and negative prognostic factor in a variety of cancers. However, the factors that contribute to its upregulation and the interaction between HOTAIR and miRNAs are largely unknown.
METHODS: A computational screen of HOTAIR promoter was conducted to search for transcription-factor-binding sites. HOTAIR promoter activities were examined by luciferase reporter assay. The function of the c-Myc binding site in the HOTAIR promoter region was tested by a promoter assay with nucleotide substitutions in the putative E-box. The association of c-Myc with the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay and Electrophoretic mobility shift assay. A search for miRNAs with complementary base paring with HOTAIR was performed utilizing online software program. Gain and loss of function approaches were employed to investigate the expression changes of HOTAIR or miRNA-130a. The expression levels of HOTAIR, c-Myc and miRNA-130a were examined in 65 matched pairs of gallbladder cancer tissues. The effects of HOTAIR and miRNA-130a on gallbladder cancer cell invasion and proliferation was tested using in vitro cell invasion and flow cytometric assays.
RESULTS: We demonstrate that HOTAIR is a direct target of c-Myc through interaction with putative c-Myc target response element (RE) in the upstream region of HOTAIR in gallbladder cancer cells. A positive correlation between c-Myc and HOTAIR mRNA levels was observed in gallbladder cancer tissues. We predicted that HOTAIR harbors a miRNA-130a binding site. Our data showed that this binding site is vital for the regulation of miRNA-130a by HOTAIR. Moreover, a negative correlation between HOTAIR and miRNA-130a was observed in gallbladder cancer tissues. Finally, we demonstrate that the oncogenic activity of HOTAIR is in part through its negative regulation of miRNA-130a.
CONCLUSION: Together, these results suggest that HOTAIR is a c-Myc-activated driver of malignancy, which acts in part through repression of miRNA-130a.

Pei CS, Wu HY, Fan FT, et al.
Influence of curcumin on HOTAIR-mediated migration of human renal cell carcinoma cells.
Asian Pac J Cancer Prev. 2014; 15(10):4239-43 [PubMed] Related Publications
BACKGROUND: This study investigated the influence of curcumin on HOX transcript antisense RNA (HOTAIR)- mediated migration of cultured renal cell carcinoma (RCC) cells.
MATERIALS AND METHODS: Five RCC cell lines (769-P, 769-P-vector, 769-P-HOTAIR, 786-0, and Kert-3 ) were maintained in vitro. The expression of HOTAIR mRNA was determined by quantitative real-time PCR and cell migration was measured by transwell migration assay. The effects of different concentrations of curcumin (0 to 80 μmol/L) on cell proliferation was determined by the CCK-8 assay and influence of non-toxic levels (0 to 10 μM) on the migration of RCC cells was also determined.
RESULTS: Comparison of the 5 cell lines indicated a correlation between HOTAIR mRNA expression and cell migration. In particular, the migration of 769-P-HOTAIR cells was significantly higher than that of 769-P-vector cells. Curcumin at 2.5-10 μM had no evident toxicity against RCC cells, but inhibited cell migration in a concentration-dependent manner.
CONCLUSIONS: HOTAIR expression is correlated with the migration of RCC cells, and HOTAIR may be involved in the curcumin-induced inhibition of RCC metastasis.

Zhang X, Weissman SM, Newburger PE
Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells.
RNA Biol. 2014; 11(6):777-87 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
HOTAIRM1 is a long intergenic non-coding RNA encoded in the human HOXA gene cluster, with gene expression highly specific for maturing myeloid cells. Knockdown of HOTAIRM1 in the NB4 acute promyelocytic leukemia cell line retarded all-trans retinoid acid (ATRA)-induced granulocytic differentiation, resulting in a significantly larger population of immature and proliferating cells that maintained cell cycle progression from G1 to S phases. Correspondingly, HOTAIRM1 knockdown resulted in retained expression of many otherwise ATRA-suppressed cell cycle and DNA replication genes, and abated ATRA induction of cell surface leukocyte activation, defense response, and other maturation-related genes. Resistance to ATRA-induced cell cycle arrest at the G1/S phase transition in knockdown cells was accompanied by retained expression of ITGA4 (CD49d) and decreased induction of ITGAX (CD11c). The coupling of cell cycle progression with temporal dynamics in the expression patterns of these integrin genes suggests a regulated switch to control the transit from the proliferative phase to granulocytic maturation. Furthermore, ITGAX was among a small number of genes showing perturbation in transcript levels upon HOTAIRM1 knockdown even without ATRA treatment, suggesting a direct pathway of regulation. These results indicate that HOTAIRM1 provides a regulatory link in myeloid maturation by modulating integrin-controlled cell cycle progression at the gene expression level.

Zhang X, Zhou L, Fu G, et al.
The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer.
Carcinogenesis. 2014; 35(9):2062-7 [PubMed] Related Publications
Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), which could induce genome-wide retargeting of polycomb-repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes, is involved in development and progression of esophageal squamous cell carcinoma (ESCC). We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, ESCC risk. Therefore, we examined the association between three haplotype-tagging SNPs (htSNP) across the whole HOTAIR locus and ESCC risk as well as the functional relevance of an ESCC susceptibility SNP rs920778. Genotypes were determined in three independent case-control sets consisted of 2098 ESCC patients and 2150 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was investigated in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.37-fold, 1.78-fold and 2.08-fold increased ESCC risk in Jinan, Shijiazhuang and Huaian populations, respectively, compared with the CC carriers (P = 0.003, 7.7 × 10(-4) and 5.9 × 10(-4)). During inspecting functional relevance of the rs920778 SNP, we identified a novel intronic HOTAIR enhancer locating between +1719bp and +2353bp from the transcriptional start site through reporter assays. Moreover, there is an allelic regulation of rs920778 on HOTAIR expression via this enhancer in both ESCC cell lines and normal esophageal tissue specimens, with higher HOTAIR expression among T allele carriers. These results demonstrate that functional genetic variants influencing lncRNA regulation may explain a fraction of ESCC genetic basis.

Liu XH, Sun M, Nie FQ, et al.
Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer.
Mol Cancer. 2014; 13:92 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
BACKGROUND: Accumulating evidence indicates that the long non-coding RNA HOTAIR plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of HOTAIR in gastric carcinogenesis remains largely unknown.
METHODS: HOTAIR expression was measured in 78 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation (RIP). The positive HOTAIR/HER2 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis.
RESULTS: HOTAIR upregulation was associated with larger tumor size, advanced pathological stage and extensive metastasis, and also correlated with shorter overall survival of gastric cancer patients. Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of gastric carcinoma cells, while HOTAIR depletion inhibited both cell invasion and cell viability, and induced growth arrest in vitro and in vivo. In particular, HOTAIR may act as a ceRNA, effectively becoming a sink for miR-331-3p, thereby modulating the derepression of HER2 and imposing an additional level of post-transcriptional regulation. Finally, the positive HOTAIR/HER2 correlation was significantly associated with advanced gastric cancers.
CONCLUSIONS: HOTAIR overexpression represents a biomarker of poor prognosis in gastric cancer, and may confer malignant phenotype to tumor cells. The ceRNA regulatory network involving HOTAIR and the positive interaction between HOTAIR and HER2 may contribute to a better understanding of gastric cancer pathogenesis and facilitate the development of lncRNA-directed diagnostics and therapeutics against this disease.

Huang J, Ke P, Guo L, et al.
Lentivirus-mediated RNA interference targeting the long noncoding RNA HOTAIR inhibits proliferation and invasion of endometrial carcinoma cells in vitro and in vivo.
Int J Gynecol Cancer. 2014; 24(4):635-42 [PubMed] Related Publications
OBJECTIVE: The overexpression of long noncoding RNA HOTAIR is associated with various aggressive solid carcinomas. However, its relationship with endometrial carcinoma has not been reported. The present study aimed to investigate the expression of the long noncoding RNA HOTAIR in endometrial carcinoma, its relationship with the carcinoma's clinicopathologic features, and the biological function of HOTAIR in regulating endometrial cancer cell proliferation and invasion in vitro and in vivo.
METHODS: The expression of HOTAIR was detected in different tissues and cell lines by real-time PCR. Lentivirus-mediated HOTAIR-specific shRNAvectors were transfected into endometrial cancer HEC-1A cells. Cell proliferation and colony formation were examined by CCK-8 assays and colony formation assays, respectively. Invasion and migration were examined by Transwell assays. Flow cytometry assay was used to examine the cell cycle. In addition, xenograft model assays were performed to analyze the growth of endometrial cancer cells in vivo.
RESULTS: Our data showed that HOTAIR expression was higher in endometrial cancer cells and tissues than in normal endometrial tissues. HOTAIR expression was closely related to the tumor stage (P = 0.045), myometrial invasion (P = 0.014), and lymph node metastasis (P = 0.033). The down-regulation of HOTAIR resulted in a significant inhibition of cell proliferation, migration, and invasion and in cell cycle arrest at the G0/G1 phase. Furthermore, HOTAIR depletion significantly suppressed the endometrial cancer tumorigenesis in vivo.
CONCLUSIONS: This study is the first to suggest that HOTAIR plays an important role in the carcinogenesis of endometrial cancer. Targeting HOTAIR may be a novel therapeutic strategy for endometrial cancer.

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