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

• Published in: Journal of molecular biology Vol. 425; no. 19; pp. 3707 - 3722
• Main Authors: Bhan, Arunoday, Hussain, Imran, Ansari, Khairul I., Kasiri, Sahba, Bashyal, Aarti, Mandal, Subhrangsu S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 09-10-2013
• Subjects: acetylation; Antisense Elements (Genetics) - genetics; Antisense Elements (Genetics) - metabolism; apoptosis; Apoptosis - drug effects; breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; cell growth; Cell Survival - drug effects; CREB-Binding Protein - genetics; CREB-Binding Protein - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-directed RNA polymerase; epigenetics; estradiol; Estradiol - pharmacology; estrogen receptors; Female; Gene Knockdown Techniques; gene overexpression; Gene Silencing; genes; Histone-Lysine N-Methyltransferase; histones; Histones - genetics; Histones - metabolism; HOTAIR; Humans; leukemia; loci; long noncoding RNA; MCF-7 Cells; Microchip Analytical Procedures; MLL histone methylases; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; non-coding RNA; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; response elements; Response Elements - drug effects; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; transcription (genetics); Transcription, Genetic; viability; HOTAIR; lncRNA; H3K27; MLL; ChIP; E2; epigenetics; CBP; DMEM; HOXC; TUNEL; H3K4; FBS; long noncoding RNA; JAM2; PBS; MLL histone methylases; RNAP II; DAPI; ER; estrogen receptors; siSENSE; PRC2; ERE; PCDHB5; homeobox C; polycomb repressive complex 2; phosphate-buffered saline; HOX antisense intergenic RNA; chromatin immunoprecipitation; CREB-binding protein; histone H3 lysine 27; estrogen response element; H3 lysine-4; protocadherin B5; estradiol; mixed lineage leukemia; estrogen receptor; 4′,6-diamidino-2-phenylindole; junction adhesion molecule 2; Dulbecco's modified Eagle's medium; fetal bovine serum; terminal dUTP nicked end labeling; small interfering sense; RNA polymerase II
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2013.01.022

HOTAIR (HOX antisense intergenic RNA) is a long noncoding RNA (lncRNA) that is transcribed from the antisense strand of homeobox C gene locus in chromosome 12. 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. We also demonstrated that 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.
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► LncRNA HOTAIR is critical for cell growth and viability. ► Knockdown of HOTAIR induces apoptosis in breast cancer cells. ► HOTAIR is transcriptionally induced by E2. ► ERs coordinate with MLLs during E2-induced HOTAIR expression. ► Results provide novel mechanistic insight of antisense strand gene expression.