Paper Title
Epigenetic Regulation of Breast Cancer-Derived Bone Metastasis and Osteoclast Differentiation

Abstract
Metastasis occurs when cancer cells from the primary tumor relocate to secondary sites, and epigenetic factors play important roles in regulating this metastatic spread event. In case of breast cancer, bone is the most common site of metastatic diseases, and more than half of all patients dying of breast cancer have evidence of osteolytic bone metastasis. Breast cancer-derived factors facilitate this bone metastatic process by generating a permissive microenvironment for cancer cell engraftment and proliferation. Histone variant incorporation at specific chromatin regions is proposed to establish distinct gene transcription states and govern cancer development and progression. Since this chromatin signaling and regulatory event has also been implicated in the control of cancer metastasis, we investigated their possible roles as regulators of metastatic potential of breast cancer cells to bone. We found that histone variant macroH2A has an intrinsic ability to inhibit breast cancer bone metastasis and osteoclast differentiation. The observed inhibitory effects require macroH2A-mediated silencing of genes encoding secreted factors that regulate metastasis, cell migration, and osteoclastogenesis. Consistent with these data, osteoclast differentiation and osteoporosis are significantly attenuated following calvarial injection of recombinant forms of secreted proteins into mice. More interestingly, our mechanistic studies reveal that macroH2A physically and functionally interacts with co-repressor Mybbp1a to inactivate metastasis-associated genes in breast cancer cells. Taken together, our data establish combinatorial roles for macroH2A and Mybbp1a in dictating bone-metastatic potential of breast cancer cells and bring new possibilities for developing therapeutic strategies to treat osteolytic bone destruction. Key words- Histone, MacroH2A, Metastasis, Bone, Osteoclast, Breast cancer.