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MacroH2A1.2 inhibits prostate cancer-induced osteoclastogenesis through cooperation with HP1α and H1.2

Oncogene volume 37, pages 5749–5765 (2018)Cite this article

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Abstract

Osteoclasts are multinuclear bone-resorbing cells that differentiate from hematopoietic precursor cells. Prostate cancer cells frequently spread to bone and secrete soluble signaling factors to accelerate osteoclast differentiation and bone resorption. However, processes and mechanisms that govern the expression of osteoclastogenic soluble factors secreted by prostate cancer cells are largely unknown. MacroH2A (mH2A) is a histone variant that replaces canonical H2A at designated genomic loci and establishes functionally distinct chromatin regions. Here, we report that mH2A1.2, one of the mH2A isoforms, attenuates prostate cancer-induced osteoclastogenesis by maintaining the inactive state of genes encoding soluble factors in prostate cancer cells. Our functional analyses of soluble factors identify lymphotoxin beta (LTβ) as a major stimulator of osteoclastogenesis and an essential mH2A1.2 target for its anti-osteoclastogenic activity. Mechanistically, mH2A1.2 directly interacts with HP1α and H1.2 and requires them to inactivate LTβ gene in prostate cancer cells. Consistently, HP1α and H1.2 have an intrinsic ability to inhibit osteoclast differentiation in a mH2A1.2-dependent manner. Together, our data uncover a new and specific role for mH2A1.2 in modulating osteoclastogenic potential of prostate cancer cells and demonstrate how this signaling pathway can be exploited to treat osteolytic bone metastases at the molecular level.

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Acknowledgements

This work was supported by NIH Grant CA201561 awarded to W.A. The study was also funded in part by pilot project grants from Keck School of Medicine of USC.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    Jin-Man Kim, Yonghwan Shin, Sunyoung Lee, Kyunghwan Kim & Woojin An

  2. Department of Microbiology, College of Medicine, Yeungnam University, Daegu, 705-717, Republic of Korea

    Mi Yeong Kim & Daewon Jeong

  3. Department of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    Vasu Punj

  4. Department of Oral Pathology, School of Dentistry, Kyungpook National University, Daegu, 700-412, Republic of Korea

    Hong-In Shin

  5. Department of Biology, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea

    Kyunghwan Kim

  6. Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea

    Jung-Min Koh

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  1. Jin-Man Kim
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Kim, JM., Shin, Y., Lee, S. et al. MacroH2A1.2 inhibits prostate cancer-induced osteoclastogenesis through cooperation with HP1α and H1.2. Oncogene 37, 5749–5765 (2018). https://doi.org/10.1038/s41388-018-0356-3

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