ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia inducible factor (HIF) family members and positively regulated HIF1a activity in TNBC. Integrated ChIP-Seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1a on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1a co-regulated genes, overexpression of AP2B1, COX20, KDM3A, or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1a signaling, therefore serving as a potential therapeutic target for TNBC.
•Sequencing data have been deposited in GEO under accession codes GSE175487
ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancerNCBI Gene Expression Omnibus, GSE175487.
Article and author information
National Cancer Institute (R01CA211732)
- Qing Zhang
National Cancer Institute (R01CA256833)
- Qing Zhang
Cancer Prevention and Research Institute of Texas (RR190058)
- Qing Zhang
American Cancer Society (RSG-18-059-01-TBE)
- Qing Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were in compliance with National Institutes of Health guidelines and were approved by the University of Texas, Southwestern Medical Center Institutional Animal Care and Use Committee.
- Caigang Liu, Shengjing Hospital of China Medical University, China
- Received: May 16, 2021
- Preprint posted: May 28, 2021 (view preprint)
- Accepted: November 14, 2021
- Accepted Manuscript published: November 15, 2021 (version 1)
- Accepted Manuscript updated: November 18, 2021 (version 2)
- Version of Record published: December 15, 2021 (version 3)
© 2021, Fang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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