The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival.
The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival.
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DOI：
10.1038/ncomms10258
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发表时间：
2016-01-05
影响因子：
16.6
通讯作者：
Anderson KC
中科院分区：
文献类型：
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作者：
Ohguchi H;Hideshima T;Bhasin MK;Gorgun GT;Santo L;Cea M;Samur MK;Mimura N;Suzuki R;Tai YT;Carrasco RD;Raje N;Richardson PG;Munshi NC;Harigae H;Sanda T;Sakai J;Anderson KC
KDM3A 与肿瘤发生有关；然而，其在多发性骨髓瘤（MM）中的生物学作用尚未阐明。在这里，我们确定了 MM 中 KDM3A–KLF2–IRF4 轴依赖性。 KDM3A 的敲低对体外和体内的 MM 细胞具有毒性。 KDM3A 通过 H3K9 去甲基化维持 KLF2 和 IRF4 的表达，敲低 KLF2 会引发细胞凋亡。此外，KLF2直接激活IRF4，IRF4交互上调KLF2，形成正向自动调节回路。 MM 细胞与骨髓环境的相互作用介导 MM 细胞的存活。重要的是，KDM3A、KLF2 或 IRF4 的沉默都会降低 MM 细胞与骨髓基质细胞的粘附，并减少 MM 细胞归巢到骨髓，与 MAF 易位 MM 细胞系中 ITGB7 表达的降低相关。我们的结果表明，KDM3A-KLF2-IRF4 通路在 MM 细胞存活和归巢至骨髓中发挥着重要作用，因此代表了一个治疗靶点。 多种组蛋白修饰剂与多发性骨髓瘤细胞的存活有关。在这里，作者揭示了组蛋白去甲基化酶 KDM3A 在这种血液癌症存活中的作用，并表明 KDM3A 从机制上消除了 KLF2 和 IRF4 启动子的 H3K9 甲基化，而 KLF2 和 IRF4 是骨髓瘤细胞存活所必需的基因。
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.