Zinc-dependent Zip7-MAZ-MYBL2 axis promotes prostate cancer metastasis.

Zinc, an essential trace element for healthy prostate, which dramatically decreases during prostate tumorigenesis. Targeting the key zinc signaling will be a valuable strategy for PCa therapy. However, the underlying mechanisms are poorly understood. Here, we show that zinc is significantly decreased in prostate cancer (PCa), especially in metastatic PCa. Screening reveals that a zinc transporter Zip7 was upregulated in metastatic PCa and related to poor progression. Zip7 silencing inhibits PCa cell migration and invasion in vitro and bone-metastasis in vivo. Mechanistically, we identify that Zip7 mainly interacts with MAZ in cytoplasm to facilitate MAZ nuclear import and nuclear MAZ was up-regulated in metastatic prostate cancer tissues and positively associated with Zip7 expression, which promotes PCa bone metastasis. Furthermore, our RNA-seq studies reveal that Zip7 facilitates MAZ nuclear import to promote MYBL2 transcription. Strikingly, we show in intraarterial injected-bone metastasis xenograft model that targeting Zip7 by its inhibitor markedly suppressed PCa bone metastasis. Collectively, our findings identify Zip7 is an important regulator of PCa metastasis and targeting Zinc-dependent Zip7-MAZ-MYBL2 could be a valuable strategy to ameliorate advanced PCa metastasis.