The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

• Published in: Nature communications 2016-01, Vol.7 (1), p.10258-15, Article 10258
• Main Authors: Ohguchi, Hiroto, Hideshima, Teru, Bhasin, Manoj K., Gorgun, Gullu T., Santo, Loredana, Cea, Michele, Samur, Mehmet K., Mimura, Naoya, Suzuki, Rikio, Tai, Yu-Tzu, Carrasco, Ruben D., Raje, Noopur, Richardson, Paul G., Munshi, Nikhil C., Harigae, Hideo, Sanda, Takaomi, Sakai, Juro, Anderson, Kenneth C.
• Format: Article
• Language: English
• Subjects: 13; 13/2; 38; 38/109; 38/15; 38/39; 38/61; 38/89; 631/337/458/1648; 631/67/1990/804; 631/80/82/23; 631/80/86; Apoptosis; Bone marrow; Cancer; Cell Adhesion - physiology; Cell cycle; Cell Line, Tumor; Cell Movement; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Gene Knockdown Techniques; Hematology; Histones - metabolism; Humanities and Social Sciences; Humans; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Medicine; Metabolism; multidisciplinary; Multiple myeloma; Multiple Myeloma - metabolism; Pathogenesis; Plasma; Proteins; Science; Science (multidisciplinary); Stem cells; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10258

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. Several histone modifiers have been implicated in the survival of multiple myeloma cells. Here, the authors reveal a role for the histone demethylase KDM3A in the survival of this haematologic cancer, and show that mechanistically KDM3A removes H3K9 methylation from the promoters of KLF2 and IRF4 , genes essential for myeloma cell survival.