Regulation of Breast Cancer-Induced Osteoclastogenesis by MacroH2A1.2 Involving EZH2-Mediated H3K27me3
Jinman Kim,
Yonghwan Shin,
Sunyoung Lee,
Miyeong Kim,
Vasu Punj,
Jason F. Lu,
Hongin Shin,
Kyunghwan Kim,
Tobias S. Ulmer,
Jungmin Koh,
Daewon Jeong,
Woojin An
Affiliations
Jinman Kim
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
Yonghwan Shin
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
Sunyoung Lee
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
Miyeong Kim
Department of Microbiology, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea
Vasu Punj
Department of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
Jason F. Lu
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
Hongin Shin
Department of Oral Pathology, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea
Kyunghwan Kim
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; Department of Biology, College of Natural Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea
Tobias S. Ulmer
Department of Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA
Jungmin Koh
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
Daewon Jeong
Department of Microbiology, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea
Woojin An
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; Corresponding author
Summary: Breast cancer cells relocate to bone and activate osteoclast-induced bone resorption. Soluble factors secreted by breast cancer cells trigger a cascade of events that stimulate osteoclast differentiation in the bone microenvironment. MacroH2A is a unique histone variant with a C-terminal non-histone domain and plays a crucial role in modulating chromatin organization and gene transcription. Here, we show that macroH2A1.2, one of the macroH2A isoforms, has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis. This repressive effect requires macroH2A1.2-dependent attenuation of expression and secretion of lysyl oxidase (LOX) in breast cancer cells. Furthermore, our mechanistic studies reveal that macroH2A1.2 physically and functionally interacts with the histone methyltransferase EZH2 and elevates H3K27me3 levels to keep LOX gene in a repressed state. Collectively, this study unravels a role for macroH2A1.2 in regulating osteoclastogenic potential of breast cancer cells, suggesting possibilities for developing therapeutic tools to treat osteolytic bone destruction. : Kim et al. demonstrate that mH2A1.2 attenuates breast cancer-induced osteoclastogenesis by maintaining the LOX gene in an inactive state. Mechanistically, mH2A1.2 recruits EZH2 to induce H3K27me3 and create a repressive barrier to LOX transcription. Keywords: macroH2A, histone, bone, osteoclast, breast cancer, LOX, Src, EZH2
