The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival

Hiroto Ohguchi, Teru Hideshima, Manoj K. Bhasin, Gullu Gorgun, Loredana Santo, Michele Cea, Mehmet K. Samur, Naoya Mimura, Rikio Suzuki, Yu Tzu Tai, Ruben D. Carrasco, Noopur Raje, Paul G. Richardson, Nikhil C. Munshi, Hideo Harigae, Takaomi Sanda, Juro Sakai, Kenneth C. Anderson

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36 Scopus citations

Abstract

KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A-KLF2-IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A-KLF2-IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

Original languageEnglish (US)
Article number10258
JournalNature Communications
Volume7
DOIs
StatePublished - Jan 5 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Ohguchi, H., Hideshima, T., Bhasin, M. K., Gorgun, G., Santo, L., Cea, M., Samur, M. K., Mimura, N., Suzuki, R., Tai, Y. T., Carrasco, R. D., Raje, N., Richardson, P. G., Munshi, N. C., Harigae, H., Sanda, T., Sakai, J., & Anderson, K. C. (2016). The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nature Communications, 7, [10258]. https://doi.org/10.1038/ncomms10258