Antisense Transcript Long Noncoding RNA (lncRNA) HOTAIR is Transcriptionally Induced by Estradiol

Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I.; Kasiri, Sahba; Bashyal, Aarti; Mandal, Subhrangsu S.

doi:10.1016/j.jmb.2013.01.022

Cited by 236 publications

(237 citation statements)

References 60 publications

Supporting

Mentioning

231

Contrasting

Unclassified

Order By: Relevance

“…HOTAIR expression is transcriptionally induced by estradiol (E2) and is potentially regulated by ERs in breast cancer (34). Bhan et al (34) found that the HOTAIR promoter contains multiple estrogen response elements.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

Bao

et al. 2013

International Journal of Molecular Medicine

100

View full text Add to dashboard Cite

Abstract. Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer. Homeobox (HOX) transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA (lncRNA), is associated with a variety of human cancers, such as breast, liver and lung cancer. However, whether HOTAIR can function as a molecular marker in endometrial carcinoma (EC) remains unknown. In the present study, the expression of HOTAIR in 66 EC tissues from patients with EC and 30 normal tissues from healthy age-matched control subjects was determined using quantitative reverse transcription PCR. Furthermore, using in situ hybridization, we measured HOTAIR expression in 129 formalin-fixed paraffin-embedded (FFPE) tissue sections, which included 96 tissues that matched the frozen cases, 21 other EC tissues and 12 atypical hyperplasia tissues. Correlations between HOTAIR expression and the clinicopathological characteristics of patients were analyzed. Our results revealed that HOTAIR expression in the EC tissues was significantly upregulated compared with normal tissues (p<0.001). In addition, we observed a significant association between HOTAIR expression and the EC grade (p<0.05) and lymph node metastasis (p<0.05). Moreover, in the FFPE tissues, but not the frozen tissues, we found that a higher HOTAIR expression also correlated with the depth of myometrial invasion (p=0.019) and lymphovascular space invasion (p=0.015). More importantly, patients with a higher HOTAIR expression showed significantly poorer overall survival than those with lower HOTAIR expression (p<0.05). In conclusion, our results suggest that a high expression of HOTAIR is involved in the progression of cancer and may be a novel biomarker of poor prognosis in patients with EC. IntroductionEndometrial carcinoma (EC) is one of the most common malignancies of the female reproductive system in Western countries. In 2013, an estimated 49,500 new cases and 8,200 deaths due to EC are expected in the USA (1). With the increase in obesity and the decrease in physical activity, the incidence of EC is rising and shows a trend in younger women (2). EC is usually classified into two types to determine the risk of metastasis and recurrence (3). Generally, type I endometrioid endometrial carcinomas (EECs) have a good prognosis and account for 80-85% of the total cases of EC. By contrast, type II non-EECs are often associated with a worse outcome (3,4). However, the prognostic value of this classification is unsatisfactory, as approximately 20% of type I tumors recur, whereas 50% of type II tumors recur (5). A number of previous studies have demonstrated the utility of molecular alterations as prognostic markers, including p53 (6), phosphatase and tensin homolog (PTEN) (7) and ; however, their value is limited (9). Thus, a deeper understanding of the molecular mechanisms responsible for EC is required for risk stratification and a clinical decision regarding individualized treatment strategies.Recent studies have indicated that only 2% of transcripts are protein-coding RNAs, and ...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Bhan et al (34) found that the HOTAIR promoter contains multiple estrogen response elements. Following treatment with E2, HOTAIR transcription is activated, and this activation is coordinated by ERs and several ER co-regulators.…”

Section: Discussionmentioning

confidence: 99%

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

Bao

et al. 2013

International Journal of Molecular Medicine

100

View full text Add to dashboard Cite

show abstract

“…Bhan [59] and colleagues found that HOTAIR knockdown in MCF7 cells resulted in upregulation of Bcl2 and BID expression, which contributed to cytochrome c release [60] and apoptotic cell death [61]. Further study demonstrated that HOTAIR expression was an estrogen-responsive gene expression and could be induced by E2 via estrogen receptors (ERs) and ER coactivators.…”

mentioning

confidence: 99%

HOTAIR: a cancer-related long non-coding RNA

Cai¹,

Song²,

Cai³

et al. 2014

neo

156

126

View full text Add to dashboard Cite

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.Key words: HOTAIR, LncRNA, HOX genes, cancer Long non-coding RNAs (LncRNAs) are commonly defined as RNA moleculars larger than 200 nucleotides. LncRNA was first found among transcribed DNA product of the mouse by Okazaki [1]. Many identified lncRNAs were transcribed by RNA polymerase II (RNA pol II) and spliced [2,3]. One view existed in the past few decades that lncRNAs were as diverse as their better known counterpart messenger RNAs (mRNAs), having no protein-coding capacity, were described as transcriptional "noise" [4,5,6]. However, a number of studies have shown that some lncRNAs were involved in embryogenesis and differentiation [7,8]. These lncRNAs are expressed in specific cell types [9, 10, 11] and located in specific subcellular compartments [12,13,14]. Moreover, recent studies have indicated that lncRNAs participated in a wide range of biological pathways and cellular processes. They could regulate gene expression and function, including dosage compensation [15,16] [18,36].HOX transcript antisense RNA (HOTAIR) is a lncRNA which has regulatory functions of transcription and are transcribed from the antisense strand of homeobox C gene locus in chromosome 12. HOTAIR recruits Polycomb Repressive Complex 2 (PRC2) and histone demethylase complex [LSD1 (lysine specific demethylase 1)/CoREST (Co-repressor of RE1-silencing transcription factor)/REST]; then leads to histone H3 tri-methylated at lysine 27 (H3K27me3) and histone H3 dimethyl Lys4 (H3K4me2); consequently results in gene silencing. In addition to its scaffold function to assemble transcription regulators, and a latest study reported that HO-TAIR could also serve as a platform to control protein levels via the ubiquitin-proteasome pathway. HOTAIR facilitated the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b, and then accelerated their degradation. Moreover, HOTAIR levels were highly upregulated in senescent cells. It

show abstract

“…This differs from the lncRNA HOTAIR which is also induced by oestrogen in breast tissue, however contains multiple oestrogen response elements (EREs) in its promoter which allow a direct response to oestrogen stimulation [341].…”

Section: Chaptermentioning

confidence: 99%

“…RNA function may also vary between cellular compartments and in response to changing conditions within the cell such as nutrient deprivation or DNA damage [351]. A full characterisation of CUPID1 and CUPID2 is beyond the scope of this thesis and will need to be addressed in subsequent studies as has been done for the lncRNA HOTAIR [254,341,354].…”

Section: Chaptermentioning

confidence: 99%

The long range regulation of breast cancer associated genes

Betts¹

View full text Add to dashboard Cite

PrefacePage iBreast cancer is the most common non-cutaneous cancer of women and a major cause of mortality [1]. Genetic factors are the single biggest risk factor and 75% of the risk derives from common but low penetrance single nucleotide polymorphisms (SNPs) [2]. These are found using genome-wide association studies (GWAS) and the majority localize to non-coding regions of the genome [3] The identification of CCND1 as an interacting partner of PRE1 and PRE2 was done using a candidate gene approach with 3C (chromosome conformation capture) targeted confirmation of interaction. To detect other potential targets of PRE1 and PRE2 at the 11q13 locus using an agnostic approach, the 4Cseq and 5C techniques were used. These revealed a number of local interaction regions covering six gene promoters. A novel strategy using knockdown of enhancer RNA transcribed from PRE1 then identified the IGHMBP2 and CPT1A genes as likely additional targets of PRE1. Genome editing with transcription activator-like effector nucleases (TALENS) was also used, creating isogenic cell lines to clarify the effects of the SNPs in their native genomic context. Further functional work is required, however the range of techniques employed has substantially expanded our understanding of the 11q13 breast cancer risk locus and forms a template for future investigations of GWAS risk loci.To identify noncoding RNAs expressed at the 11q13 locus that may be interacting with PRE1 or PRE2 required the use of RNA Capture-seq. RNA Capture-seq involves a targeted enrichment step that greatly increases the sequencing depth at regions of interest and can reveal lowly expressed transcripts that may have not been found by traditional RNA-seq [7]. This identified one novel long non-coding RNA expressed from the (+) strand that was named CUPID1 and a second arising from the same locus on the (-) strand named CUPID2. They were located in the nucleus, oestrogen induced and both expressed relatively highly in ERα positive breast cancer cell lines but not in ERα The 11q13 locus is amplified in around 20% of breast cancers and is thought to contain a number of driver genes including CCND1 [8]. Given that CUPID1 and CUPID2 are widely over-expressed inERα positive breast cancer cell lines, it was hypothesized that they may also have a role in driving tumour growth. Publically available RNAseq data showed CUPID2 to be highly expressed in breast and renal cancer but not in normal tissue. Stable cell lines over-expressing the lncRNAs were then generated and subsequent oncogenic assays revealed that CUPID2 increased cellular proliferation and the efficiency of colony formation in breast cancer cells. A murine xenograft model confirmed these findings in vivo by demonstrating a marked increase in tumour size for the mice injected with cells over-expressing CUPID2. There is thus evidence that CUPID2 behaves as an oncogene and may be an additional driver of the 11q13 amplicon in ERα positive breast cancer.In summary, CPT1A and IGHMBP2 were identified as potential mediat...

show abstract

Antisense Transcript Long Noncoding RNA (lncRNA) HOTAIR is Transcriptionally Induced by Estradiol

Cited by 236 publications

References 60 publications

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

HOTAIR: a cancer-related long non-coding RNA

The long range regulation of breast cancer associated genes

Contact Info

Product

Resources

About

Antisense Transcript Long Noncoding RNA (lncRNA) HOTAIR is Transcriptionally Induced by Estradiol

Cited by 236 publications

References 60 publications

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

HOTAIR: a cancer-related long non-coding RNA

The long range regulation of breast cancer associated genes

Contact Info

Product

Resources

About

HOTAIR: a cancer-related long non-coding RNA