PMID- 34359722
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210809
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 15
DP  - 2021 Jul 29
TI  - A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer.
LID - 10.3390/cancers13153821 [doi]
LID - 3821
AB  - 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 (HIF1alpha) 
      and endothelial growth factor A (VEGFA) as functional downstream mediators of 
      HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1alpha 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.
FAU - Fan, Qipeng
AU  - Fan Q
AD  - Department of Obstetrics and Gynecology, Indiana University School of Medicine, 
      950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA.
FAU - Li, Lihong
AU  - Li L
AD  - Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 600 
      North Wolfe St., Baltimore, MD 21287, USA.
FAU - Wang, Tian-Li
AU  - Wang TL
AD  - Department of Gynecology, Oncology, and Pathology, Johns Hopkins Medical 
      Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA.
FAU - Emerson, Robert E
AU  - Emerson RE
AD  - 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.
FAU - Xu, Yan
AU  - Xu Y
AUID- ORCID: 0000-0001-8445-7996
AD  - Department of Obstetrics and Gynecology, Indiana University School of Medicine, 
      950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA.
LA  - eng
PT  - Journal Article
DEP - 20210729
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8345154
OTO - NOTNLM
OT  - ZIP4
OT  - cancer stem cell (CSC)
OT  - endothelial growth factor A (VEGFA)
OT  - high-grade serous ovarian cancer (HGSOC)
OT  - histone deacetylase 4 (HDAC4)
COIS- All authors declare no conflicts of interest. The authors are solely responsible 
      for the study design, data collection, analysis and interpretation of data, 
      writing the manuscript, and the decision to submit the manuscript for 
      publication.
EDAT- 2021/08/08 06:00
MHDA- 2021/08/08 06:01
PMCR- 2021/07/29
CRDT- 2021/08/07 01:03
PHST- 2021/07/14 00:00 [received]
PHST- 2021/07/25 00:00 [accepted]
PHST- 2021/08/07 01:03 [entrez]
PHST- 2021/08/08 06:00 [pubmed]
PHST- 2021/08/08 06:01 [medline]
PHST- 2021/07/29 00:00 [pmc-release]
AID - cancers13153821 [pii]
AID - cancers-13-03821 [pii]
AID - 10.3390/cancers13153821 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Jul 29;13(15):3821. doi: 10.3390/cancers13153821.