ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer
- The First Affiliated Hospital of Nanjing Medical University, China
- University of Texas Southwestern Medical Center, United States
- University of North Carolina School of Medicine, United States
- The University of Alabama at Birmingham, United States
- Shanghai Jiao Tong University School of Medicine, China
- The University of Texas Health Science Center at Houston McGovern Medical School, United States
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan
- The University of Texas Southwestern Medical Center, United States
- Department of Pathology, University of Texas Southwestern Medical Center, United States
- National Tsing Hua University, Taiwan
Abstract
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.
Data availability
•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
Author details
Christopher Llynard Ortiz
Funding
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.
Reviewing Editor
- Caigang Liu, Shengjing Hospital of China Medical University, China
Ethics
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.
Version history
- 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)
Copyright
© 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.
Metrics
-
- 1,503
- views
-
- 251
- downloads
-
- 21
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer
eLife 10:e70412.
https://doi.org/10.7554/eLife.70412
Further reading
-
- Cancer Biology
Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome of E. coli colonized in murine tumors. Compared to E. coli cultivated in the rich medium, we found that E. coli colonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment to E. coli. We also found that the colonization of E. coli in the tumor led to an increased expression of lipocalin 2 (LCN2), a host protein that can sequester the enterobactin. We therefore engineered E. coli in order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, the E. coli synthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. coli showed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. coli treatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria’s ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.
-
- Cancer Biology
- Cell Biology
Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.
