ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer
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Evaluation Summary:
This study identifies ZHX2 as an oncogenic factor in triple negative breast cancer (TNBC), which interferes with hypoxia-related regulators and accounts for cancer aggressiveness and poor prognosis. The authors show that ZHX2 interacts with HIF1α and increases the expression of its downstream targets and identify ZHX2 residues critical for regulating its activity. This work provides a potential novel target in TNBC treatment and would be of interest to cancer biology researchers.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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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 HIF1α activity in TNBC. Integrated ChIP-seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1α coregulated 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 HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.
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Evaluation Summary:
This study identifies ZHX2 as an oncogenic factor in triple negative breast cancer (TNBC), which interferes with hypoxia-related regulators and accounts for cancer aggressiveness and poor prognosis. The authors show that ZHX2 interacts with HIF1α and increases the expression of its downstream targets and identify ZHX2 residues critical for regulating its activity. This work provides a potential novel target in TNBC treatment and would be of interest to cancer biology researchers.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This study reports the function of ZHX2 as a new oncogene in triple negative breast cancer. Large amount of work was conducted to validate its role in promoting cancer progression, and detailed analysis revealed the mechanism of ZHX2 interfering with HIF and activating downstream transcription. However, experimental in vivo data and the mechanistic exploration could be strengthened.
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Reviewer #2 (Public Review):
In this manuscript, authors report that ZHX2 is upregulated in TNBC patients and cell lines. Several aggressive attributes of TNBC cells including proliferation, migration/invasion, and orthotopic tumor growth and spontaneous lung metastasis, require ZHX2 expression. The authors have used integrated ChIP-seq and RNA-seq analysis to show that ZHX2 is co-occupied with HIF1α on transcriptionally active promoter sites. Furthermore, the authors have used molecular modelling and site directed mutagenesis to establish that R491, R581, and R674 residues on ZHX2 are crucial for regulating HIF1 activity and downstream functions. Overall, the manuscript is (mostly) well written and the claims are well supported by the data. The data, however, is heavily reliant on in vitro cell-based models and lacks validation in TNBC …
Reviewer #2 (Public Review):
In this manuscript, authors report that ZHX2 is upregulated in TNBC patients and cell lines. Several aggressive attributes of TNBC cells including proliferation, migration/invasion, and orthotopic tumor growth and spontaneous lung metastasis, require ZHX2 expression. The authors have used integrated ChIP-seq and RNA-seq analysis to show that ZHX2 is co-occupied with HIF1α on transcriptionally active promoter sites. Furthermore, the authors have used molecular modelling and site directed mutagenesis to establish that R491, R581, and R674 residues on ZHX2 are crucial for regulating HIF1 activity and downstream functions. Overall, the manuscript is (mostly) well written and the claims are well supported by the data. The data, however, is heavily reliant on in vitro cell-based models and lacks validation in TNBC mouse models or data from human tumors.
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Reviewer #3 (Public Review):
Dysregulated expression of ZHXs has recently been reported in several cancer types, and ZHX2 is involved in carcinogenesis and cancer progression. In this manuscript, the authors perform a study on the molecular mechanisms how ZHX2 regulated TNBC progression. CHIP-Seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1a promoters and promote gene expression, the evidences are solid and provide a potential target for breast cancer therapy.
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