Targeting ONECUT2 inhibits tumor angiogenesis via down-regulating ZKSCAN3/VEGFA

• Published in: Biochemical pharmacology Vol. 225; p. 116315
• Main Authors: Zhang, Ligang, Li, Cunjie, Song, Xinran, Guo, Raoqing, Zhao, Wenli, Liu, Chunyan, Chen, Xi, Song, Qifang, Wu, Binhua, Deng, Ning
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-07-2024
• Subjects: Angiogenesis; OC-2; Target therapy; Tumor; VEGFA; ZKSCAN3; Angiogenesis; OC-2 KD; IHC; Target therapy; qRT-PCR; ZKSCAN3; Tumor; ChIP; OC-2; WT; VEGFA; OC-2 OE
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116315

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OC-2 plays a vital role in tumor growth, metastasis and angiogenesis, but molecular mechanism how OC-2 regulates angiogenic factors is unclear. We found that OC-2 was highly expressed in HepG2, COLO, MCF-7, SKOV3 cells and rectum carcinoma tissues, and angiogenic factors levels were positively related to OC-2. Then OC-2 KD inhibited the tumor growth, metastasis and angiogenesis process in vitro and vivo. ChIP-Seq showed that 228 target genes of OC-2 were identified and they were associated with tumor growth, metastasis, angiogenesis and signal transduction; OC-2 bound to ZKSCAN3 at promoter region. Luciferase assays showed that ZKSCAN3 was identified as target gene of OC-2 and VEGFA was identified as target gene of ZKSCAN3; OC-2 promoted VEGFA expression via activating ZKSCAN3 transcriptional program. Importantly, OC-2 KD down-regulated VEGFA secretion to suppress tumor angiogenesis of HUVECs. Besides VEGFA, OC-2 was positively correlated with other angiogenic factors HIF-1α, FGF2, EGFL6 and HGF. Meanwhile, ERK1/2 and Smad1 signaling pathways might be related to function of OC-2 driving tumor aggressiveness. We revealed that OC-2 might regulate tumor growth, metastasis, angiogenesis via ERK1/2, Smad1 signaling pathways and regulate VEGFA expression for tumor angiogenesis via activating ZKSCAN3 transcriptional program, indicating that OC-2 was a convincing target to develop novel anti-tumor drugs based on angiogenesis.