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

Cancers

Lihong Li¹  Tian-Li Wang²  Yan Xu³  Qipeng Fan³  Robert E. Emerson⁴ 

[1] Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 600 North Wolfe St., Baltimore, MD 21287, USA;Department of Gynecology, Oncology, and Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA;Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA;Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indiana University Health Pathology Laboratory, 350 W. 11th Street, Room 4010, Indianapolis, IN 46202, USA;

关键词: cancer stem cell (CSC);    histone deacetylase 4 (HDAC4);    high-grade serous ovarian cancer (HGSOC);    endothelial growth factor A (VEGFA);    ZIP4;   

DOI  :  10.3390/cancers13153821

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown