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Multiple Myeloma, Gammopathies

KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival

Leukemia volume 31, pages 2661–2669 (2017)Cite this article

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Abstract

Recent studies have delineated cancer-type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in multiple myeloma (MM) cells; and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6B abrogate MM cell growth and survival. Tumor necrosis factor-α or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting that KDM6B is regulated by NF-κB signaling in MM cells. RNA-seq and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1 and FOS, and upregulates expression of these genes without affecting H3K27 methylation level. Overexpression of catalytically inactive KDM6B activates expression of MAPK pathway-related genes, confirming its function independent of demethylase activity. We further demonstrate that downstream targets of KDM6B, ELK1 and FOS, confer MM cell growth. Our study therefore delineates KDM6B function that links NF-κB and MAPK signaling pathway mediating MM cell growth and survival, and validates KDM6B as a novel therapeutic target in MM.

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Acknowledgements

We thank Dr John Quackenbush and members of the Center for Cancer Computational Biology, Dana-Farber Cancer Institute for assistance with RNA-seq analysis. This research was supported by NIH grants SPORE P50-CA100707 (KCA), P01-CA078378 (KCA), R01-CA050947 (KCA) and R01-CA178264 (T Hideshima and KCA). KCA is an American Cancer Society Clinical Research Professor.

Author contributions

HO designed and performed experiments, analyzed the data and wrote the manuscript; T Harada, MS and SK analyzed the data; Y-TT and PGR provided clinical samples. T Hideshima and KCA analyzed the data and edited the manuscript.

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    H Ohguchi, T Harada, M Sagawa, S Kikuchi, Y-T Tai, P G Richardson, T Hideshima & K C Anderson

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  1. H Ohguchi
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Correspondence to K C Anderson.

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Ohguchi, H., Harada, T., Sagawa, M. et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia 31, 2661–2669 (2017). https://doi.org/10.1038/leu.2017.141

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