The breast cancer antiestrogen resistance 4 (BCAR4) gene is an inducer of tamoxifen resistance in tumor cells, and its expression correlates with cancer aggressiveness. Yang and colleagues now show that the BCAR4 transcript is a lncRNA that promotes metastasis by activating the expression of a cell-migration pathway. lncRNA array screens and quantitative RNA analyses revealed that BCAR4 was the most highly upregulated lncRNA in breast cancer tissues, and its expression correlated with metastasis in multiple cancer cell types. BCAR4 knockdown in breast cancer cell lines specifically reduced expression of genes controlled by the Hedgehog signaling pathway, whose regulatory proteins include the kinase citron (CIT) and transcription factors GLI2, PNUTS and SNIP1. PNUTS and SNIP1 directly bind distinct regions of BCAR4 in RNA pulldown assays, whereas CIT and GLI2 interact with the lncRNA via SNIP1. CIT phosphorylates GLI2 at Ser149, and this phospho-GLI2 form is enriched within the BCAR4 complex and in invasive breast cancer tissues. A screen of chemokines known to activate CIT kinase in breast cancer cell lines revealed that CCL21, previously implicated in breast cancer metastasis, induced CIT-dependent GLI2 phosphorylation and nuclear translocation. In the nucleus, GLI2 directs expression of genes involved in cell migration. Indeed, phospho-GLI2 and BCAR4 bind CCL21-induced genes in ChIP assays and are required for their expression. Knockdown of BCAR4 or its associated proteins inhibits cell migration, thus supporting the central role of this lncRNA in the signaling pathway. Moreover, BCAR4-SNIP1 binding precludes SNIP1 interactions with p300, which would repress the acetyltransferase activity of the latter. This leads to increased histone acetylation at CCL21-induced genes. Intriguingly, the authors show that acetylated histones are recognized by PNUTS, which inhibits PP1 phosphatase activity at the RNA Pol II C-terminal domain, thus suggesting a potential means for BCAR4 to regulate transcription. The current findings, together with the demonstration that BCAR4 can be efficiently depleted with locked nucleic acid (LNA) antisense oligonucleotides, underscore the potential of new cancer therapies that target lncRNAs. (Cell 159, 1110–1125, 2014)