Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress
Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress
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髓样锌指 1 (MZF-1) 通过促进铁转运蛋白传导的铁排出来抑制前列腺肿瘤生长
DOI：
10.1038/onc.2014.310
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发表时间：
2015-07-01
期刊：
影响因子：
8
通讯作者：
Liu, S.
中科院分区：
文献类型：
--
作者：
Chen, Y.;Zhang, Z.;Liu, S.
虽然先前的研究表明，髓样锌指1（MZF-1）是一个多方面的转录因子，可能作为一个致癌基因或肿瘤抑制因子，决定其不同性状的分子基础仍然难以捉摸。越来越多的证据表明，铁代谢障碍影响肿瘤的发生和肿瘤的行为，并且过量的肿瘤铁通过各种机制刺激肿瘤进展，例如增强DNA复制和能量代谢。膜铁转运蛋白（FPN）是哺乳动物细胞中唯一已知的铁输出蛋白，它决定了铁从细胞中的整体排出。FPN减少导致铁外排减少和细胞内铁增加，从而增强铁的致癌作用。MZF-1最近被鉴定为调节FPN表达的转录因子。然而，到目前为止，癌症中MZF-1-FPN信号转导的分子机制在很大程度上是未知的。在这里，我们发现前列腺肿瘤中FPN水平相对于邻近组织显著降低，并证明了FPN通过控制肿瘤铁浓度在肿瘤生长中的关键作用。MZF-1表达的抑制导致FPN浓度降低，伴随产生的细胞内铁潴留，增加铁相关的细胞活性和增强肿瘤细胞生长。相反，MZF-1表达的增加通过促进FPN驱动的铁排出抑制肿瘤细胞生长。重要的是，我们证明了AP 4和c-Myb共同调节MZF-1的转录，并且miR-492也通过结合其mRNA的3′非翻译区直接参与调节MZF-1的浓度。与导致MZF-1和FPN减少的邻近组织相比，这些结果与前列腺肿瘤中发现的AP 4和c-Myb表达减少和miR-492表达升高相关。此外，我们证明了AP 4，c-Myb和miR-492水平的改变显著影响肿瘤细胞的生长。因此，靶向MZF-1-FPN信号传导内的分子似乎是抑制前列腺癌的有希望的方法。
Although previous studies suggest that myeloid zinc-finger 1 (MZF-1) is a multifaceted transcription factor that may function as either an oncogene or a tumor suppressor, the molecular bases determining its different traits remain elusive. Increasing evidence suggests that disorders in iron metabolism affect tumorigenesis and tumor behaviors, and that excess tumor iron stimulates tumor progression through various mechanisms such as enhancing DNA replication and energy metabolism. Ferroportin (FPN) is the only known iron exporter in mammalian cells, and it determines global iron egress out of cells. FPN reduction leads to decreased iron efflux and increased intracellular iron that consequentially aggravates the oncogenic effects of iron. MZF-1 was recently identified as a transcription factor that regulates FPN expression. Thus far, however, the molecular mechanisms underlying the MZF-1–FPN signaling in cancers are largely unknown. Here, we found a significant reduction of FPN levels in prostate tumors relative to adjacent tissues, and demonstrated a crucial role of FPN in tumor growth through controlling tumor iron concentration. Inhibition of MZF-1 expression led to reduced FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth. In contrast, increase of MZF-1 expression restrained tumor cell growth by promoting FPN-driven iron egress. Importantly, we demonstrated that AP4 and c-Myb jointly modulated MZF-1 transcription, and that miR-492 was also directly involved in regulating MZF-1 concentration through binding to the 3′ untranslated regions of its mRNA. These results correlate with reduced AP4 and c-Myb expression and elevated miR-492 expression found in prostate tumors as compared with adjacent tissues that resulted in diminished MZF-1 and FPN. Moreover, we demonstrated that alterations of AP4, c-Myb and miR-492 levels significantly affected tumor cell growth. Targeting molecules within the MZF-1–FPN signaling thus appears to be a promising approach to restrain prostate cancer.