Binding of the JmjC Demethylase JARID1B to LSD1/NuRD Suppresses Angiogenesis and Metastasis in Breast Cancer Cells by Repressing Chemokine CCL14

JARID1B is a member of the JmjC/ARID family of demethylases that specifically demethylates tri- and di-methylated forms of histone H3 lysine 4 (H3K4) that are associated with active genes. JARID1B expression is dysregulated in several cancers in which it has been implicated, but how it might affect tumor progression is unclear. In this study, we report that JARID1B is a physical component of the LSD1/NuRD complex that functions in transcriptional repression. JARID1B and LSD1 acted in a sequential and coordinated manner to demethylate H3K4. A genome-wide transcriptional analysis revealed that among the cellular signaling pathways targeted by the JARID1B/LSD1/NuRD complex is the CCL14 chemokine pathway of cell migration and angiogenesis. JARID1B repressed the expression of CCL14, an epithelial derived chemokine, suppressing the angiogenic and metastatic potential of breast cancer cells in vivo. Our findings indicate that CCL14 is a critical mediator of the JARID1B/LSD1/NuRD complex in regulation of angiogenesis and metastasis in breast cancer, identifying a novel potential therapeutic target for breast cancer intervention. Cancer Res; 71(21); 6899-908. (C) 2011 AACR.