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HOTAIR: Hox antisense intergenic RNA
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 .. HOTAIR acts as a scaffold for protein complexes. A 5' domain binds PRC2 while a 3' domain binds LSD1. Oncogene - regulates metastatic progression .. 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 . 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 .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 .HOTAIR methylation is not altered in cancer cells . 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.It has been reported that HOTAIR expression is correlated with SUZ12 expression level and therefore may affect the epigenetic state of cancer tissues.
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. 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.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. Reduced expression of HOTAIR in KATO III suppressed peritoneal dissemination suggest that HOTAIR plays a pivotal role in the development of gastric cancer. 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. 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 .HOTAIR is a potential biomarker for ESCC prognosis, and the dysregulation of HOTAIR may play an important role in ESCC progression.
HOTAIR exists in mammals but with poor sequence conservation .. A 239 bp domain in HOTAIR exon 6 is especially conserved in mammals . 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 . 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 .
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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.
The long non-coding RNA HOTAIR has been reported to be a poor prognostic biomarker in a variety of malignant tumors. 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. 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.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. HOTAIR as an inducer of ubiquitin-mediated proteolysis on post-translational function. 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. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. HOTAIR levels are highly upregulated in senescent cells, causing rapid decay of targets Ataxin-1 and Snurportin-1, and preventing premature senescence.HOTAIR, as a platform for protein ubiquitination.
Allelic Information and Variation
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Labs working on this lncRNA
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, Maryland 21224, USA.
- Rinn JL1, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY.(2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.Cell. 2007 Jun 29;129(7):1311-23.
- Tsai MC1, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY.(2010) Long noncoding RNA as modular scaffold of histone modification complexes.Science. 2010 Aug 6;329(5992):689-93. doi: 10.1126/science.1192002. Epub 2010 Jul 8.
- Gupta RA1, 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. (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.Nature. 2010 Apr 15;464(7291):1071-6. doi: 10.1038/nature08975.
- Schorderet P1, Duboule D.(2011)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. Epub 2011 May 26.
- Thomas Amort, Marie F. Soulière, Alexandra Wille, Xi-Yu Jia, Heidi Fiegl, Hildegard Wörle, Ronald Micura, Alexandra Lusser. (2013) Long non-coding RNAs as targets for cytosine methylation.PLoS One. 2013 May 23;8(5):e63516. doi: 10.1371/journal.pone.0063516. Print 2013.
- Bhan A1, Hussain I, Ansari KI, Kasiri S, Bashyal A, Mandal SS. (2013) 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. Epub 2013 Jan 31.
- Hajjari M1, Behmanesh M, Sadeghizadeh M, Zeinoddini M.(2013)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. Epub 2013 Jul 26.
- Kogo R1, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, Tanaka F, Shibata K, Suzuki A, Komune S, Miyano S, Mori M. (2013) 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. Epub 2011 Aug 23.
- Khalil AM1, 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. (2009) 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. Epub 2009 Jul 1.
- Tani H1, Mizutani R, Salam KA, Tano K, Ijiri K, Wakamatsu A, Isogai T, Suzuki Y, Akimitsu N.(2012) 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. Epub 2012 Feb 27.
- Chiyomaru T1, 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. Print 2013.
- Cui L1, Xie XY, Wang H, Chen XL, Liu SL, Hu LN.(2013)[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.
- Endo H1, 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. eCollection 2013.
- Li D1, Feng J, Wu T, Wang Y, Sun Y, Ren J, Liu M.(2013)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. Epub 2012 Nov 7.
- Liu Z1, Sun M, Lu K, Liu J, Zhang M, Wu W, De W, Wang Z, Wang R.(2013)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. eCollection 2013.
- Lv XB1, Lian GY, Wang HR, Song E, Yao H, Wang MH.(2013) 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. Print 2013.
- He S1, Liu S, Zhu H.(2011) 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.
- Ge XS1, Ma HJ, Zheng XH, Ruan HL, Liao XY, Xue WQ, Chen YB, Zhang Y, Jia WH.(2013) 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. Epub 2013 Oct 30.
- Liu XH1, Liu ZL, Sun M, Liu J, Wang ZX, De W.(2013) 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.
- Yoon JH1, Abdelmohsen K, Kim J, Yang X, Martindale JL, Tominaga-Yamanaka K, White EJ, Orjalo AV, Rinn JL, Kreft SG, Wilson GM, Gorospe M.(2013) Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. BMC Cancer. Nat Commun. 2013;4:2939. doi: 10.1038/ncomms3939.