Abstract
Angiogenesis is a hallmark of tumorigenesis, and hepatocellular carcinoma (HCC) is hypervascular and therefore very dependent on angiogenesis for tumor development and progression. Findings from previous studies suggest that in HCC cells, hypoxia-induced factor 1α (HIF1A) and zinc finger homeobox 3 (ZFHX3) transcription factors functionally interact in the regulation of genes in HCC cells. Here, we report that hypoxia increases the transcription of the ZFHX3 gene and enhances the binding of HIF1A to the ZFHX3 promoter in the HCC cell lines HepG2 and Huh-7. Moreover, ZFHX3, in turn, physically associated with and was functionally indispensable for HIF1A to exert its angiogenic activity, as indicated by in vitro migration and tube formation assays of human umbilical vein endothelial cells (HUVECs) and microvessel formation in xenograft tumors of HCC cells. Mechanistically, ZFHX3 was required for HIF1A to transcriptionally activate the vascular endothelial growth factor A (VEGFA) gene by binding to its promoter. Functionally, down-regulation of ZFHX3 in HCC cells slowed their tumor growth, and addition of VEGFA to conditioned medium from ZFHX3-silenced HCC cells partially rescued the inhibitory effect of this medium on HUVEC tube formation. In human HCC, ZFHX3 expression was up-regulated, and this up-regulation correlated with both HIF1A up-regulation and worse patient survival, confirming a functional association between ZFHX3 and HIF1A in human HCC. We conclude that ZFHX3 is an angiogenic transcription factor that is integral to the HIF1A/VEGFA signaling axis in HCC cells.
Highlights
Angiogenesis is a hallmark of tumorigenesis, and hepatocellular carcinoma (HCC) is hypervascular and very dependent on angiogenesis for tumor development and progression
We conclude that zinc finger homeobox 3 (ZFHX3) is an angiogenic transcription factor that is integral to the Hypoxia-induced factor-1A (HIF1A)/ vascular endothelial growth factor A (VEGFA) signaling axis in HCC cells
We found that the expression of ZFHX3 was significantly increased by hypoxia via the binding of HIF1A to ZFHX3’s promoter in HCC cells, and ZFHX3 became necessary for the angiogenic activity of HIF1A via transcriptional activation of the VEGFA angiogenic effector
Summary
The transcription factor ZFHX3 is crucial for the angiogenic function of hypoxia-inducible factor 1␣ in liver cancer cells. Findings from previous studies suggest that in HCC cells, hypoxia-induced factor 1␣ (HIF1A) and zinc finger homeobox 3 (ZFHX3) transcription factors functionally interact in the regulation of genes in HCC cells. The transcription of AFP in HCC cells is downregulated under hypoxic conditions via the binding of HIF1A to the AFP promoter [12], which suggests that ZFHX3 could functionally associate with HIF1A in gene regulation tumor angiogenesis. In HCC, ZFHX3 is infrequently quencing; GEPIA, Gene Expression Profiling Interactive Analysis; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase In human HCCs, higher levels of ZFHX3 expression correlated with higher HIF1A expression and worse disease-free survival These findings indicate that ZFHX3 is integral to HIF1A function in HCC angiogenesis
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