Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States; Department of Genetics, Neuroscience Center; University of North Carolina School of Medicine, Chapel Hill, United States
Travis S Ptacek
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States; UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, United States
Giada Zurlo
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
Youqiong Ye
Shanghai Institute of Immunology, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Leng Han
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, United States
Cheng Fan
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States
Lei Bao
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taiwan; Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan
Hong-Rui Lin
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
Ujjawal Manocha
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States
Weibo Luo
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
Yan Peng
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
William Y Kim
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taiwan; Physics Division, National Center for Theoretical Sciences, Hsinchu, Taiwan
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.
