ZHX2 promotes 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 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.

Zinc fingers and homeoboxes 2 is required for diethylnitrosamine‐induced liver tumor formation in C57BL/6 mice

“…[ 49 ] In contrast to these tumors, Zhx2 is oncogenic in clear‐cell renal cell carcinoma, the most common kidney tumor, potentially through co‐regulation of target genes with NF‐κB, [ 50 ] and in triple‐negative breast cancer, where it co‐regulates target genes with hypoxia inducible factor 1 alpha subunit. [ 51 ] Future studies will require different liver tumor model systems to fully understand Zhx2 control of tumor initiation and promotion. Because Zhx2 is known to regulate many genes that control lipid homeostasis, and that obesity and NAFLD are currently major drivers of the increased incidence of HCC, it will be particularly interesting to investigate the role of Zhx2 in high‐fat diet–induced liver tumor models.…”

Zinc Fingers and Homeoboxes 2 is Required for Diethylnitrosamine-induced Liver Tumor Formation in C57BL/6 Mice

“…Zhx2 inhibits the metastatic potential of several thyroid cancer cell lines, possibly by inhibition of S100A14, suggesting a tumor suppressor role in this cancer (49). In contrast to these tumors, Zhx2 is oncogenic in clear cell Renal Cell Carcinoma, the most common kidney tumor, potentially through co-regulation of target genes with NF-κB (50), and in triple-negative breast cancer, where it co-regulates target genes with HIF1a (51). Future studies will require different liver tumor model systems to fully understand Zhx2 control of tumor initiation and promotion.…”

Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity

“…Given an importance of hypoxia signaling in tumor progression and cell metabolism, the present studies are mainly focused on investigating the effects of HIF1α binding partners in affecting these processes ( 65 ) ( 19 , 58 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ). In fact, the roles of hypoxia signaling in hypoxia adaptation and tolerance have been noticed, particularly for high-altitude adaptation ( 77 , 78 , 79 , 80 , 81 ).…”