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.
Keywords: 4′,6-diamidino-2-phenylindole; CBP; CREB-binding protein; ChIP; DAPI; DMEM; Dulbecco's modified Eagle's medium; E2; ER; ERE; FBS; H3 lysine-4; H3K27; H3K4; HOTAIR; HOX antisense intergenic RNA; HOXC; JAM2; MLL; MLL histone methylases; PBS; PCDHB5; PRC2; RNA polymerase II; RNAP II; TUNEL; chromatin immunoprecipitation; epigenetics; estradiol; estrogen receptor; estrogen receptors; estrogen response element; fetal bovine serum; histone H3 lysine 27; homeobox C; junction adhesion molecule 2; lncRNA; long noncoding RNA; mixed lineage leukemia; phosphate-buffered saline; polycomb repressive complex 2; protocadherin B5; siSENSE; small interfering sense; terminal dUTP nicked end labeling.
Published by Elsevier Ltd.