NONHSAT028508

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Annotated Information

Name

HOTAIR: Hox antisense intergenic RNA

Characteristics

2.2 kb; spliced, polyadenylated and comprised of 6 exons in humans .Transcribed from the HOXC locus from a position intergenic and antisense to the flanking HOXC11 and HOXC12 genes . Expression Expressed in posterior and distal fibroblasts . Expression level in cancer is an efficient predictor of metastasis and survival with high expression levels predictive of poor outcomes . Also in patients with stage IV colorectal cancer (CRC), HOTAIR expression levels were higher in cancerous tissues than in noncancerous tissues, with high HOTAIR expression tightly correlated with the presence of liver metastasis and associated with poor prognosis . Some HOTAIR transcripts localise to the nucleus .In situ hybridization analysis of the mouse cognate RNA (mHotair) showed expression similar to Hoxc11, with distinct levels in parts of the proximal hindlimbs, genital bud and tail in embryos at E11.5, as well as in in posterior part of the hindlimb and genital bud at E12.5 . Transcript found to be quite unstable with a half-life >4 hr in human Hela cells.

Function

Originally identified as silencing the HoxD locus but has since been found to epigenetic silence gene expression at many sites across the genome by recruitment of PRC2 and LSD1/CoREST/REST repressive chromatin modifying complexes (Rinn (2007), Tsai (2010)). HOTAIR acts as a scaffold for protein complexes. A 5' domain binds PRC2 while a 3' domain binds LSD1 [v (Tsai (2010))]. Oncogene - regulates metastatic progression (Gupta (2010))(Schorderet (2011)). HOTAIR dysregulated in breast cancer with frequent overexpression in metastases. Overexpression of HOTAIR leads to PRC2 re-targeting across the genome to a state similar to that in embryonic fibroblasts, promoting tumour invasion and metatasis. Oncogenic effects of HOTAIR upregulation were dependent on PRC2 (Gupta (2010)). Deletion of the HoxC cluster containing the cognate Hotair transcript in mouse showed little phenotypic effect, with little change in the expression on levels of H3K27me3 coverage in corresponding human HOTAIR Hoxd target genes (Schorderet (2011)). Several species, such as the mammalian XIST or HOTAIR RNAs, have been suggested to function at the chromatin level by interacting with chromatin modifying protein complexes (Amort T (2013)).HOTAIR methylation is not altered in cancer cells (Amort T (2013)). HOTAIR coordinates with chromatin-modifying enzymes and regulates gene silencing. It is overexpressed in various carcinomas including breast cancer. Herein, we demonstrated that HOTAIR is crucial for cell growth and viability and its knockdown induced apoptosis in breast cancer cells(Bhan A 2013).It has been reported that HOTAIR expression is correlated with SUZ12 expression level and therefore may affect the epigenetic state of cancer tissues(Hajjari M 2013). .

Expression

Expressed in posterior and distal fibroblasts (Rinn (2007)). Expression level in cancer is an efficient predictor of metastasis and survival with high expression levels predictive of poor outcomes (Gupta (2010)). Also in patients with stage IV colorectal cancer (CRC), HOTAIR expression levels were higher in cancerous tissues than in noncancerous tissues, with high HOTAIR expression tightly correlated with the presence of liver metastasis and associated with poor prognosis (Kogo (2011)) . Some HOTAIR transcripts localise to the nucleus (Khalil (2009)). In situ hybridization analysis of the mouse cognate RNA (mHotair) showed expression similar to Hoxc11, with distinct levels in parts of the proximal hindlimbs, genital bud and tail in embryos at E11.5, as well as in in posterior part of the hindlimb and genital bud at E12.5 (Schorderet (2011)). Transcript found to be quite unstable with a half-life >4 hr in human Hela cells (Tani (2012)). There is site-specific cytosine methylation in the lncRNA HOTAIR. Methylation of C1683 is widespread in different cell types and it is not limited by the abundance of HOTAIR RNA levels. Furthermore, the degree of methylation of C1683 appears to be remarkably high, suggesting that it might be important for the function of HOTAIR. In this respect, it is interesting to note that C1683 is located in the vicinty of the region that has previously been shown to interact with the LSD1 complex.It is therefore tempting to speculate thatmethylation of this cytosine may affect the ability of HOTAIR to interact with LSD1.LncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells.(Chiyomaru T 2013).RNA HOTAIR expressions were higher in ovarian cancer; it may play a role in ovarian cancer, and become a biomarker for malignant degree of ovarian cancer and may provide a novel therapeutic target for ovarian cancer.(Cui, L 2013). Reduced expression of HOTAIR in KATO III suppressed peritoneal dissemination suggest that HOTAIR plays a pivotal role in the development of gastric cancer(Endo H 2013). HOTAIR plays an oncogenic role in human laryngeal squamous cell cancer (LSCC),HOTAIR levels were significantly higher in LSCC than in corresponding adjacent non-neoplastic tissues,HOTAIR is an independent prognostic factor of LSCC.(Li D). HOTAIR expression was significantly upregulated in cisplatin-resistant A549/DDP cells compared with in parental A549 cells. Knockdown of HOTAIR by RNA interference could resensitize the responses of A549/DDP cells to cisplatin both in vitro and in vivo. In contrast, overexpression of HOTAIR could decrease the sensitivity of A549 and SPC-A1 cells to cisplatin. We also found that the siRNA/HOTAIR1-mediated chemosensivity enhancement was associated with inhibition of cell proliferation, induction of G0/G1 cell-cycle arrest and apoptosis enhancement through regulation of p21(WAF1/CIP1) (p21) expression. Also, pcDNA/p21or siRNA/p21 could mimic the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on the sensitivity of LAD cells to cisplatin. Importantly, siRNA/p21 or pcDNA/p21 could partially rescue the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on both p21 expression and cisplatin sensitivity in LAD cells. Further, HOTAIR was observed to be significantly downregulated in cisplatin-responding LAD tissues, and its expression was inversely correlated with p21 mRNA expression. Taken together, our findings suggest that upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression(Liu Z).HOTAIR is a potential biomarker for ESCC prognosis, and the dysregulation of HOTAIR may play an important role in ESCC progression(Lv XB).

Conservation

HOTAIR exists in mammals but with poor sequence conservation (Rinn (2007))(He (2011)). A 239 bp domain in HOTAIR exon 6 is especially conserved in mammals (He (2011)). The mouse EST (AK035706) homologous to human HOTAIR is comprised of two exons only, with the second half of the first exon showing similarity to exon 4 of HOTAIR, whereas the second exon is homologous to exon 6 of HOTAIR (Schorderet (2011)). This may underlie differences in function since the first three exons of HOTAIR (absent from mHotair) contain binding sites for EZH2, while the 3' extremity of human HOTAIR that interact with LSD1 is part of the least conserved DNA sequence within mHotair exon 2 (Schorderet (2011)).

Misc

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Transcriptomic Nomeclature

HOTAIR is transcriptionally induced by estradiol (E2). Its promoter contains multiple functional estrogen response elements (EREs). Estrogen receptors (ERs) along with various ER coregulators such as histone methylases MLL1 (mixed lineage leukemia 1) and MLL3 and CREB-binding protein/p300 bind to the promoter of HOTAIR in an E2-dependent manner. Level of histone H3 lysine-4 trimethylation, histone acetylation, and RNA polymerase II recruitment is enriched at the HOTAIR promoter in the presence of E2. Knockdown of ERs and MLLs downregulated the E2-induced HOTAIR expression. Thus, similar to protein-coding gene transcription, E2-induced transcription of antisense transcript HOTAIR is coordinated via ERs and ER coregulators, and this mechanism of HOTAIR overexpression potentially contributes towards breast cancer progression.(Bhan A 2013)

Regulation

The long non-coding RNA HOTAIR has been reported to be a poor prognostic biomarker in a variety of malignant tumors(Endo H 2013). There was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro(Ge XS 2013). Aberrant up-regulation of HOTAIR in gastric adenocarcinoma samples compared with normal adjacent gastric epithelium tissues. Besides, the aberrant expression of HOTAIR was associated with TNM staging and lymph node metastasis of gastric tumors. Here, a potential cooperative expression between HOTAIR and SUZ12 genes in gastric adenocarcinoma tissues is deduced(Hajjari M 2013). HOTAIR upregulation was correlated with NSCLC advanced pathological stage and lymph-node metastasis, HOTAIR is significantly up-regulated in NSCLC tissues, and regulates NSCLC cell invasion and metastasis, partially via the down-regulation of HOXA5. Thus, HOTAIR may represent a new marker of poor prognosis and is a potential therapeutic target for NSCLC intervention(Liu XH 2013).

Allelic Information and Variation

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Evolution

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Labs working on this lncRNA

Department of Oncology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.

Basic Information

Transcript ID	NONHSAT028508
Source	NONCODE4.0
Same with	,
Classification	intergenic
Length	2337 nt
Genomic location	chr12-:54356092..54362540
Exon number	6
Exons	54356092..54357908,54358015..54358067,54359748..54359871,54360060..54360161,54361053..54361178,54362401..54362540
Genome context
Sequence	000001 ACATTCTGCC CTGATTTCCG GAACCTGGAA GCCTAGGCAG GCAGTGGGGA ACTCTGACTC GCCTGTGCTC TGGAGCTTGA 000080 000081 TCCGAAAGCT TCCACAGTGA GGACTGCTCC GTGGGGGTAA GAGAGCACCA GGCACTGAGG CCTGGGAGTT CCACAGACCA 000160 000161 ACACCCCTGC TCCTGGCGGC TCCCACCCGG GACTTAGACC CTCAGGTCCC TAATATCCCG GAGGTGCTCT CAATCAGAAA 000240 000241 GGTCCTGCTC CGCTTCGCAG TGGAATGGAA CGGATTTAGA AGCCTGCAGT AGGGGAGTGG GGAGTGGAGA GAGGGAGCCC 000320 000321 AGAGTTACAG ACGGCGGCGA GAGGAAGGAG GGGCGTCTTT ATTTTTTTAA GGCCCCAAAG AGTCTGATGT TTACAAGACC 000400 000401 AGAAATGCCA CGGCCGCGTC CTGGCAGAGA AAAGGCTGAA ATGGAGGACC GGCGCCTTCC TTATAAGTAT GCACATTGGC 000480 000481 GAGAGAAGTG CTGCAACCTA AACCAGCAAT TACACCCAAG CTCGTTGGGG CCTAAGCCAG TACCGACCTG GTAGAAAAAG 000560 000561 CAACCACGAA GCTAGAGAGA GAGCCAGAGG AGGGAAGAGA GCGCCAGACG AAGGTGAAAG CGAACCACGC AGAGAAATGC 000640 000641 AGGCAAGGGA GCAAGGCGGC AGTTCCCGGA ACAAACGTGG CAGAGGGCAA GACGGGCACT CACAGACAGA GGTTTATGTA 000720 000721 TTTTTATTTT TTAAAATCTG ATTTGGTGTT CCATGAGGAA AAGGGAAAAT CTAGGGAACG GGAGTACAGA GAGAATAATC 000800 000801 CGGGTCCTAG CTCGCCACAT GAACGCCCAG AGAACGCTGG AAAAACCTGA GCGGGTGCCG GGGCAGCACC CGGCTCGGGT 000880 000881 CAGCCACTGC CCCACACCGG GCCCACCAAG CCCCGCCCCT CGCGGCCACC GGGGCTTCCT TGCTCTTCTT ATCATCTCCA 000960 000961 TCTTTATGAT GAGGCTTGTT AACAAGACCA GAGAGCTGGC CAAGCACCTC TATCTCAGCC GCGCCCGCTC AGCCGAGCAG 001040 001041 CGGTCGGTGG GGGGACTGGG AGGCGCTAAT TAATTGATTC CTTTGGACTG TAAAATATGG CGGCGTCTAC ACGGAACCCA 001120 001121 TGGACTCATA AACAATATAT CTGTTGGGCG TGAGTGCACT GTCTCTCAAA TAATTTTTCC ATAGGCAAAT GTCAGAGGGT 001200 001201 TCTGGATTTT TAGTTGCTAA GGAAAGATCC AAATGGGACC AATTTTAGGA GGCCCAAACA GAGTCCGTTC AGTGTCAGAA 001280 001281 AATGCTTCCC CAAAGGGGTT GGGAGTGTGT TTTGTTGGAA AAAAGCTTGG GTTATAGGAA AGCCTTTCCC TGCTACTTGT 001360 001361 GTAGACCCAG CCCAATTTAA GAATTACAAG GAAGCGAAGG GGTTGTGTAG GCCGGAAGCC TCTCTGTCCC GGCTGGATGC 001440 001441 AGGGGACTTG AGCTGCTCCG GAATTTGAGA GGAACATAGA AGCAAAGGTC CAGCCTTTGC TTCGTGCTGA TTCCTAGACT 001520 001521 TAAGATTCAA AAACAAATTT TTAAAAGTGA AACCAGCCCT AGCCTTTGGA AGCTCT