NONHSAT028508

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HOTAIR epigenetically silence gene expression at many sites across the genome by recruitment of chromatin modifying complexes and the abnormal expression of HOTAIR is highly correlated with the development of many kinds of human cancers.

Annotated Information

Name

HOTAIR: Hox antisense intergenic RNA

Characteristics

2.2 kb; spliced, polyadenylated and comprised of 6 exons in humans [1].

Transcribed from the HOXC locus from a position intergenic and antisense to the flanking HOXC11 and HOXC12 genes [1].

Some HOTAIR transcripts localise to the nucleus [2].

Transcript found to be quite unstable with a half-life >4 hr in human Hela cells[3].

Function

Changes in mRNA and occupancy of H3K4me2, H3K27me3, LSD1, and SUZ12 across HOXD locus after RNAi of HOTAIR in foreskin fibroblasts. Yellow boxes indicate regions of notable correlation between gain of H3K4me2 and concordant loss of LSD1, H3K27me3, and SUZ12. [4]

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 [1][4].

HOTAIR has been suggested to function at the chromatin level by interacting with chromatin modifying protein complexes [5]. It has been reported that HOTAIR expression is correlated with SUZ12 expression level and therefore may affect the epigenetic state of cancer tissues[6]. HOTAIR acts as a scaffold for protein complexes. A 5' domain binds PRC2 while a 3' domain binds LSD1[4]. Oncogenic effects of HOTAIR upregulation were dependent on PRC2 [7].

Oncogene - regulates metastatic progression in many kinds of cancers [7][8][9][10][11][6]. It is crucial for cell growth and viability and its knockdown induced apoptosis in breast cancer cells[12]. There was a great upregulation of HOTAIR in Esophageal squamous cell carcinoma (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[9]. Knockdown of HOTAIR decreased prostate cancer (PCa) cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest [10]. High HOTAIR expression tightly correlated with the presence of liver metastasis and associated with poor prognosis [11]. The aberrant expression of HOTAIR was associated with TNM staging and lymph node metastasis of gastric tumors[6]. Reduced expression of HOTAIR in KATO III suppressed peritoneal dissemination suggest that HOTAIR plays a pivotal role in the development of gastric cancer[13].

It is also highly correlated with malignant degree of cancer and the therapeutic effect [14][7][15][16][17].

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 [8].

HOTAIR acts as an inducer of ubiquitin-mediated proteolysis on post-translational function[18]. HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. HOTAIR levels are highly upregulated in senescent cells, causing rapid decay of targets Ataxin-1 and Snurportin-1, and preventing premature senescence[18].

Expression

Expressed in posterior and distal fibroblasts [1].

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 [8].

It is up-regulated in breast cancer [7][12], colorectal cancer (CRC) [11], Esophageal squamous cell carcinoma (ESCC) [9], ovarian cancer [14], gastric adenocarcinoma samples [6],Non-small-cell lung carcinoma (NSCLC) [15], laryngeal squamous cell cancer (LSCC) [16],cisplatin-resistant A549/DDP cells [19].

Conservation

HOTAIR exists in mammals but with poor sequence conservation [1][20]. A 239 bp domain in HOTAIR exon 6 is especially conserved in mammals [20].

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 [8]. 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 [8].

Regulation

HOTAIR is transcriptionally induced by estradiol (E2). 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[12]. The long non-coding RNA HOTAIR has been reported to be a poor prognostic biomarker in a variety of malignant tumors[13].

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. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells[10].

There is site-specific cytosine methylation in the lncRNA HOTAIR. Methylation of C1683 may affect the ability of HOTAIR to interact with LSD1[5].

Allelic Information and Variation

Please input allelic information and variation information here.

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Labs working on this lncRNA

Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, Maryland 21224, USA [18].

Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China [20].

Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo, Japan [3].

School of Life Sciences, Federal Institute of Technology, Lausanne, Switzerland [8].

The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA [2].

Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan [11].

Howard Hughes Medical Institute and Program in Epithelial Biology, California 94305, USA [7][4].

Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA [1].

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.Cell. 2007 Jun 29;129(7):1311-23.
  2. ↑ 2.0 2.1 Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11667-72. doi: 10.1073/pnas.0904715106.
  3. ↑ 3.0 3.1 Tani H, Mizutani R, Salam KA, Tano K, Ijiri K, Wakamatsu A, Isogai T, Suzuki Y, Akimitsu N. Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals.Genome Res. 2012 May;22(5):947-56. doi: 10.1101/gr.130559.111.
  4. ↑ 4.0 4.1 4.2 4.3 Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes.Science. 2010 Aug 6;329(5992):689-93. doi: 10.1126/science.1192002.
  5. ↑ 5.0 5.1 Thomas Amort, Marie F. Soulière, Alexandra Wille, Xi-Yu Jia, Heidi Fiegl, Hildegard Wörle, Ronald Micura, Alexandra Lusser. Long non-coding RNAs as targets for cytosine methylation.PLoS One. 2013 May 23;8(5):e63516. doi: 10.1371/journal.pone.0063516.
  6. ↑ 6.0 6.1 6.2 6.3 Hajjari M, Behmanesh M, Sadeghizadeh M, Zeinoddini M. Up-regulation of HOTAIR long non-coding RNA in human gastric adenocarcinoma tissues.Med Oncol. 2013;30(3):670. doi: 10.1007/s12032-013-0670-0.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.Nature. 2010 Apr 15;464(7291):1071-6.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Schorderet P1, Duboule D.Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet. 2011 May;7(5):e1002071. doi: 10.1371/journal.pgen.1002071.
  9. ↑ 9.0 9.1 9.2 Ge XS, Ma HJ, Zheng XH, Ruan HL, Liao XY, Xue WQ, Chen YB, Zhang Y, Jia WH. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway.Cancer Sci. 2013 Dec;104(12):1675-82. doi: 10.1111/cas.12296.
  10. ↑ 10.0 10.1 10.2 Chiyomaru T, Yamamura S, Fukuhara S, Yoshino H, Kinoshita T, Majid S, Saini S, Chang I, Tanaka Y, Enokida H, Seki N, Nakagawa M, Dahiya R.(2013)Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS One. 2013 Aug 1;8(8):e70372. doi: 10.1371/journal.pone.0070372.
  11. ↑ 11.0 11.1 11.2 11.3 Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, Tanaka F, Shibata K, Suzuki A, Komune S, Miyano S, Mori M. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011 Oct 15;71(20):6320-6. doi: 10.1158/0008-5472.CAN-11-1021.
  12. ↑ 12.0 12.1 12.2 Bhan A, Hussain I, Ansari KI, Kasiri S, Bashyal A, Mandal SS. Antisense transcript long noncoding RNA (lncRNA) HOTAIR is transcriptionally induced by estradiol. J Mol Biol. 2013 Oct 9;425(19):3707-22. doi: 10.1016/j.jmb.2013.01.022.
  13. ↑ 13.0 13.1 Endo H, Shiroki T, Nakagawa T, Yokoyama M, Tamai K, Yamanami H, Fujiya T, Sato I, Yamaguchi K, Tanaka N, Iijima K, Shimosegawa T, Sugamura K, Satoh K.(2013) Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer. PLoS One. 2013 Oct 10;8(10):e77070. doi: 10.1371/journal.pone.0077070.
  14. ↑ 14.0 14.1 Cui L, Xie XY, Wang H, Chen XL, Liu SL, Hu LN. [Expression of long non-coding RNA HOTAIR mRNA in ovarian cancer].Sichuan Da Xue Xue Bao Yi Xue Ban. 2013 Jan;44(1):57-9.
  15. ↑ 15.0 15.1 Liu XH, Liu ZL, Sun M, Liu J, Wang ZX, De W. The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer. 2013 Oct 8;13:464. doi: 10.1186/1471-2407-13-464.
  16. ↑ 16.0 16.1 Li D, Feng J, Wu T, Wang Y, Sun Y, Ren J, Liu M. Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma.Am J Pathol. 2013 Jan;182(1):64-70. doi: 10.1016/j.ajpath.2012.08.042.
  17. ↑ Lv XB, Lian GY, Wang HR, Song E, Yao H, Wang MH. Long noncoding RNA HOTAIR is a prognostic marker for esophageal squamous cell carcinoma progression and survival.PLoS One. 2013 May 23;8(5):e63516. doi: 10.1371/journal.pone.0063516.
  18. ↑ 18.0 18.1 18.2 Yoon JH, Abdelmohsen K, Kim J, Yang X, Martindale JL, Tominaga-Yamanaka K, White EJ, Orjalo AV, Rinn JL, Kreft SG, Wilson GM, Gorospe M. Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination.Nat Commun. 2013;4:2939. doi: 10.1038/ncomms3939.
  19. ↑ Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, De W, Wang Z, Wang R. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One. 2013 Oct 14;8(10):e77293. doi: 10.1371/journal.pone.0077293.
  20. ↑ 20.0 20.1 20.2 He S, Liu S, Zhu H. The sequence, structure and evolutionary features of HOTAIR in mammals. BMC Evol Biol. 2011 Apr 16;11:102. doi: 10.1186/1471-2148-11-102.


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 AGCTCTTGAA GGTTCAGCAC CCACCCAGGA 001600
001601 ATCCACCTGC CTGTTACACG CCTCTCCAAG ACACAGTGGC ACCGCTTTTC TAACTGGCAG CACAGAGCAA CTCTATAATA 001680
001681 TGCTTATATT AGGTCTAGAA GAATGCATCT TGAGACACAT GGGTAACCTA ATTATATAAT GCTTGTTCCA TACAGGAGTG 001760
001761 ATTATGCAGT GGGACCCTGC TGCAAACGGG ACTTTGCACT CTAAATATAG ACCCCAGCTT GGGACAAAAG TTGCAGTAGA 001840
001841 AAAATAGACA TAGGAGAACA CTTAAATAAG TGATGCATGT AGACACAGAA GGGGTATTTA AAAGACAGAA ATAATAGAAG 001920
001921 TACAGAAGAA CAGAAAAAAA ATCAGCAGAT GGAGATTACC ATTCCCAATG CCTGAACTTC CTCCTGCTAT TAAGATTGCT 002000
002001 AGAGAATTGT GTCTTAAACA GTTCATGAAC CCAGAAGAAT GCAATTTCAA TGTATTTAGT ACACACACAG TATGTATATA 002080
002081 AACACAACTC ACAGAATATA TTTTCCATAC ATTGGGTAGG TATGCACTTT GTGTATATAT AATAATGTAT TTTCCATGCA 002160
002161 GTTTTAAAAT GTAGATATAT TAATATCTGG ATGCATTTTC TGTGCACTGG TTTTATATGC CTTATGGAGT ATATACTCAC 002240
002241 ATGTAGCTAA ATAGACTCAG GACTGCACAT TCCTTGTGTA GGTTGTGTGT GTGTGGTGGT TTTATGCATA AATAAAGTTT 002320
002321 TACATGTGGT GAAAAAA
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