The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment
The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment
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DOI：
10.1038/leu.2016.358
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发表时间：
2017-07-01
期刊：
影响因子：
11.4
通讯作者：
Podar, K.
中科院分区：
文献类型：
--
作者：
Fan, F.;Bashari, M. H.;Podar, K.
尽管治疗取得了进展，但多发性骨髓瘤(MM)仍然是一种无法治愈的疾病，主要原因是耐药性的产生。激活蛋白-1(AP-1)转录因子家族参与了多种生理过程和肿瘤的发生，但其在多发性骨髓瘤中的作用尚不清楚。在这里，我们展示了当与骨髓基质细胞共培养时，AP-1家族成员JunB在MM细胞中的特异性和快速诱导。支持JunB在MM发病机制中的关键作用的基因敲除后，在体外显著抑制了MM细胞的增殖和存活。一贯地，在微环境的小鼠MM模型中，诱导沉默JunB显著减少了肿瘤的生长。随后的基因表达谱揭示了与凋亡、DNA复制和代谢相关的基因在驱动MM细胞JunB介导的表型中的作用。重要的是，在地塞米松耐药的MM细胞中，JunB基因的敲除恢复了对地塞米松的反应。此外，4-羟基他莫昔芬诱导的JunB-ER融合蛋白的激活可以保护对地塞米松敏感的MM细胞免受地塞米松和硼替佐米诱导的细胞毒性。综上所述，我们的结果首次证明了AP-1/JunB在MM细胞的增殖、存活和耐药中的特定作用，从而有力地支持了该转录因子是MM治疗的一个有前景的新靶点。
Despite therapeutic advances, multiple myeloma (MM) remains an incurable disease, predominantly because of the development of drug resistance. The activator protein-1 (AP-1) transcription factor family has been implicated in a multitude of physiologic processes and tumorigenesis; however, its role in MM is largely unknown. Here we demonstrate specific and rapid induction of the AP-1 family member JunB in MM cells when co-cultured with bone marrow stromal cells. Supporting a functional key role of JunB in MM pathogenesis, knockdown of JUNB significantly inhibited in vitro MM cell proliferation and survival. Consistently, induced silencing of JUNB markedly decreased tumor growth in a murine MM model of the microenvironment. Subsequent gene expression profiling revealed a role for genes associated with apoptosis, DNA replication and metabolism in driving the JunB-mediated phenotype in MM cells. Importantly, knockdown of JUNB restored the response to dexamethasone in dexamethasone-resistant MM cells. Moreover, 4-hydroxytamoxifen-induced activation of a JunB-ER fusion protein protected dexamethasone-sensitive MM cells against dexamethasone-and bortezomib-induced cytotoxicity. In summary, our results demonstrate for the first time a specific role for AP-1/JunB in MM cell proliferation, survival and drug resistance, thereby strongly supporting that this transcription factor is a promising new therapeutic target in MM.