Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Researchers identified that the lincRNA HOTAIR is dysregulated in breast cancer progression, with increased expression in primary tumors and metastases. HOTAIR levels in primary tumors are a strong predictor of metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells reprograms the chromatin state by altering the occupancy of the Polycomb Repressive Complex 2 (PRC2), leading to changes in histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis. Conversely, loss of HOTAIR inhibits cancer invasiveness, particularly in cells with high PRC2 activity. These findings suggest that lincRNAs play an active role in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy. HOTAIR binds to and targets the PRC2 complex to the HOXD locus, leading to H3K27 trimethylation and epigenetic silencing of metastasis suppressor genes. The study also shows that HOTAIR-induced PRC2 occupancy patterns resemble those of embryonic fibroblasts, reprogramming the chromatin state of breast epithelial cells. The interdependence between HOTAIR and PRC2 has therapeutic implications, as high levels of HOTAIR may identify tumors sensitive to PRC2 inhibitors. Understanding the molecular mechanisms by which HOTAIR regulates PRC2 is critical for exploring new cancer therapies. The study used various methods, including RNA expression analysis, gene transfer experiments, and in vivo assays, to demonstrate the role of HOTAIR in promoting cancer metastasis. The findings highlight the importance of lincRNAs in cancer progression and suggest that targeting HOTAIR could be a promising therapeutic strategy.Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Researchers identified that the lincRNA HOTAIR is dysregulated in breast cancer progression, with increased expression in primary tumors and metastases. HOTAIR levels in primary tumors are a strong predictor of metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells reprograms the chromatin state by altering the occupancy of the Polycomb Repressive Complex 2 (PRC2), leading to changes in histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis. Conversely, loss of HOTAIR inhibits cancer invasiveness, particularly in cells with high PRC2 activity. These findings suggest that lincRNAs play an active role in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy. HOTAIR binds to and targets the PRC2 complex to the HOXD locus, leading to H3K27 trimethylation and epigenetic silencing of metastasis suppressor genes. The study also shows that HOTAIR-induced PRC2 occupancy patterns resemble those of embryonic fibroblasts, reprogramming the chromatin state of breast epithelial cells. The interdependence between HOTAIR and PRC2 has therapeutic implications, as high levels of HOTAIR may identify tumors sensitive to PRC2 inhibitors. Understanding the molecular mechanisms by which HOTAIR regulates PRC2 is critical for exploring new cancer therapies. The study used various methods, including RNA expression analysis, gene transfer experiments, and in vivo assays, to demonstrate the role of HOTAIR in promoting cancer metastasis. The findings highlight the importance of lincRNAs in cancer progression and suggest that targeting HOTAIR could be a promising therapeutic strategy.