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 journalArticlepeer-review

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 languageEnglish (US)
Article numbere70412
JournaleLife
Volume10
DOIs
StatePublished - 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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