The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

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.

Hypoxia-inducible KDM3A addiction in multiple myeloma

“…29 However, our data suggested that IRF4 is not an essential target of KDM3A, at least in hypoxia, for the following reasons. First, although KDM3A expression was very weak in normoxia, but markedly increased in hypoxia, IRF4 expression was suppressed by hypoxia.…”

“…Demethylated H3K9 is known to increase transcriptional activity, 34 and several transcriptional targets of KDM3A in cancer have been identified. 24,29,35 However, most of the "hypoxiaspecific" transcriptional targets of KDM3A are unknown in myeloma oncogenesis. Our data suggested that MALAT1 could be a target of KDM3A in myeloma oncogenesis under hypoxia.…”

“…Furthermore, we investigated whether any stimulation from the microenvironment other than hypoxia affects the H3K9 demethylase Figure 4C-D). Although it has been reported that KDM3A, an H3K9 demethylase containing a jumonji domain, plays an important oncogenic role in cancer, [27][28][29] the exact role of KDM3A in the hypoxic stress response of myeloma has not been reported. We therefore sought to investigate the role of KDM3A in hypoxia.…”

“…Changes in expression were also examined under hypoxic conditions to identify a reduction compared with the hypoxia-subjected GFP-scramble cells (Figure 3C-D). In addition, because KDM3A has been reported to positively regulate IRF4, 29 we examined IRF4 expression. Although IRF4 expression is reduced by hypoxia, its expression was not affected by shKDM3A in any of the myeloma cell lines (U266, RPMI-8226, and KMS-11; Figure 3D; supplemental Figure 5A).…”

The potential of KDM3A as a therapeutic target in Ewing Sarcoma and other cancers

“…Recently, a number of studies have implicated KDM3A (JMJD1A/JHDM2A), a member of the KDM3 subfamily with specificity for removal of mono and di-methyl marks from H3K9, in tumor/metastasis promotion, chemoresistance and other phenotypes, in cancers of epithelial origin (including the common cancers of breast 4 , prostate 5 and colon 6 ), liver 7 , and the hematopoietic system 8 . Additionally, recent studies have implicated KDM3A in solid malignancies of childhood, including the metastasis of neuroblastoma 9 , a malignant pediatric tumor of peripheral nervous system origin, and both tumorigenesis and metastasis of Ewing Sarcoma 10, 11 , a pediatric sarcoma of bone and soft tissue.…”