Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
J Mol Biol. 2013 Oct 9;425(19):3707-22. doi: 10.1016/j.jmb.2013.01.022. Epub 2013 Jan 31.
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.
HOTAIR（HOX 反义基因间 RNA）是一种长链非编码 RNA（lncRNA），它从 12 号染色体同源盒 C 基因座的反义链转录而来。HOTAIR 与染色质修饰酶协同作用，调节基因沉默。它在各种癌中过表达，包括乳腺癌。在此，我们证明 HOTAIR 对细胞生长和活力至关重要，其敲低可诱导乳腺癌细胞凋亡。我们还证明 HOTAIR 受雌二醇（E2）转录诱导。其启动子包含多个功能雌激素反应元件（EREs）。雌激素受体（ERs）与各种 ER 共激活因子（如组蛋白甲基转移酶 MLL1（混合谱系白血病 1）和 MLL3 以及 CREB 结合蛋白/p300）一起，以 E2 依赖的方式结合到 HOTAIR 启动子上。在 E2 存在的情况下，HOTAIR 启动子上的组蛋白 H3 赖氨酸 4 三甲基化、组蛋白乙酰化和 RNA 聚合酶 II 募集水平丰富。ERs 和 MLLs 的敲低下调了 E2 诱导的 HOTAIR 表达。因此，与蛋白质编码基因转录类似，E2 诱导的反义转录本 HOTAIR 的转录通过 ERs 和 ER 共激活因子协调，这种 HOTAIR 过表达的机制可能有助于乳腺癌的进展。
