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.