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Published on: August 14, 2019
Targeting ONECUT2 inhibits tumor angiogenesis via down-regulating ZKSCAN3/VEGFA
Ligang Zhang1, Cunjie Li2, Xinran Song2
1Guangdong Province Engineering Research Center for Antibody Drug and Immunoassay, Department of Biology, Jinan University, Guangzhou 510632, China; School of Medicine, Foshan University, Foshan 528225, China.
Abstract:
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.
Insights
OC-2 promotes tumor growth and angiogenesis by activating ZKSCAN3 to increase VEGFA expression. Inhibiting OC-2 (OC-2 KD) suppressed tumor progression and angiogenesis, revealing OC-2 as a potential anti-cancer drug target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- OC-2 is implicated in tumor growth, metastasis, and angiogenesis.
- The precise molecular mechanisms by which OC-2 regulates angiogenic factors remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of OC-2 in regulating angiogenic factors.
- To investigate the role of OC-2 in tumor growth, metastasis, and angiogenesis.
- To identify OC-2 as a potential therapeutic target for anti-angiogenesis cancer drugs.
Main Methods:
- Expression analysis of OC-2 in cancer cell lines and tissues.
- OC-2 knockdown (KD) experiments in vitro and in vivo.
- Chromatin immunoprecipitation sequencing (ChIP-Seq) to identify OC-2 target genes.
- Luciferase reporter assays to confirm gene targets and regulatory pathways.
- Analysis of angiogenic factors and signaling pathways (ERK1/2, Smad1).
Main Results:
- OC-2 expression was high in HepG2, COLO, MCF-7, SKOV3 cells, and rectum carcinoma tissues, correlating positively with angiogenic factor levels.
- OC-2 KD significantly inhibited tumor growth, metastasis, and angiogenesis.
- ChIP-Seq identified 228 OC-2 target genes involved in tumor progression and signal transduction.
- OC-2 directly binds to ZKSCAN3, promoting VEGFA expression via the ZKSCAN3 transcriptional program.
- OC-2 KD reduced VEGFA secretion, suppressing tumor angiogenesis in HUVECs.
- OC-2 correlated with angiogenic factors HIF-1α, FGF2, EGFL6, and HGF.
- ERK1/2 and Smad1 signaling pathways were implicated in OC-2's role in tumor aggressiveness.
Conclusions:
- OC-2 drives tumor growth, metastasis, and angiogenesis, partly by activating the ZKSCAN3-VEGFA pathway.
- OC-2 regulates tumor aggressiveness through ERK1/2 and Smad1 signaling.
- OC-2 is a promising therapeutic target for developing novel anti-angiogenesis drugs.
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