A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

SIMPLE SUMMARY: Despite tremendous research efforts, epithelial ovarian cancer (EOC) remains one of the most difficult cancers to detect early and treat successfully for >5-year survival. We have recently shown that ZIP4, a zinc transporter, is a novel cancer stem cell (CSC) marker and a therapeutic target for EOC. The current work focuses on developing new strategies to target ZIP4 and inhibit its CSC activities in EOC. We found that cells expressing high levels of ZIP4 were supersensitive to a group of inhibitors called HDACis. One of the major targets of these inhibitors is a protein called HDAC4. We revealed the new molecular bases for the ZIP4-HDAC4 axis and tested the efficacies of targeting this axis in the lab and in mouse models. Our study provides a new mechanistic-based targeting strategy for EOC. ABSTRACT: We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC.