Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress

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.