ZHX2 prom 1 otes hif1α oncogenic signaling in triple-negative breast cancer

Wentong Fang; Chengheng Liao; Rachel Shi; Jeremy M. Simon; Travis S. Ptacek; Giada Zurlo; Youqiong Ye; Leng Han; Cheng Fan; Christopher Llynard Ortiz; Hong Rui Lin; Ujjawal Manocha; Weibo Luo; Yan Peng; William Y. Kim; Lee Wei Yang; Qing Zhang

doi:10.7554/eLife.70412

ZHX2 prom 1 otes hif1α oncogenic signaling in triple-negative breast cancer

Wentong Fang, Chengheng Liao, Rachel Shi, Jeremy M. Simon, Travis S. Ptacek, Giada Zurlo, Youqiong Ye, Leng Han, Cheng Fan, Christopher Llynard Ortiz, Hong Rui Lin, Ujjawal Manocha, Weibo Luo, Yan Peng, William Y. Kim, Lee Wei Yang, Qing Zhang

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling HIF1α activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.

Original language	English (US)
Article number	e70412
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.70412
State	Published - Nov 2021

Keywords

HIF1α
TNBC
VHL
ZHX2

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.7554/eLife.70412

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@article{07250eb173764697b83b9920cb50ec84,

title = "ZHX2 prom 1 otes hif1α oncogenic signaling in triple-negative breast cancer",

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. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling HIF1α activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.",

keywords = "HIF1α, TNBC, VHL, ZHX2",

author = "Wentong Fang and Chengheng Liao and Rachel Shi and Simon, {Jeremy M.} and Ptacek, {Travis S.} and Giada Zurlo and Youqiong Ye and Leng Han and Cheng Fan and Ortiz, {Christopher Llynard} and Lin, {Hong Rui} and Ujjawal Manocha and Weibo Luo and Yan Peng and Kim, {William Y.} and Yang, {Lee Wei} and Qing Zhang",

note = "Funding Information: This work was supported in part by the National Cancer Institute (Q.Z., R01CA211732 and Publisher Copyright: {\textcopyright} 2021, eLife Sciences Publications Ltd. All rights reserved.",

year = "2021",

month = nov,

doi = "10.7554/eLife.70412",

language = "English (US)",

volume = "10",

journal = "eLife",

issn = "2050-084X",

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T1 - ZHX2 prom 1 otes hif1α oncogenic signaling in triple-negative breast cancer

AU - Fang, Wentong

AU - Liao, Chengheng

AU - Shi, Rachel

AU - Simon, Jeremy M.

AU - Ptacek, Travis S.

AU - Zurlo, Giada

AU - Ye, Youqiong

AU - Han, Leng

AU - Fan, Cheng

AU - Ortiz, Christopher Llynard

AU - Lin, Hong Rui

AU - Manocha, Ujjawal

AU - Luo, Weibo

AU - Peng, Yan

AU - Kim, William Y.

AU - Yang, Lee Wei

AU - Zhang, Qing

PY - 2021/11

Y1 - 2021/11

N2 - 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. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling HIF1α activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.

AB - 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. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling HIF1α 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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KW - TNBC

KW - VHL

KW - ZHX2

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ZHX2 prom 1 otes hif1α oncogenic signaling in triple-negative breast cancer

Abstract

Keywords

ASJC Scopus subject areas

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