CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy
Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1alpha at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.
| Errataetall: |
CommentIn: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):E190; author reply E191. - PMID 21169507 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:107 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 107(2010), 32 vom: 10. Aug., Seite 14484-9 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
de Nigris, Filomena [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.09.2010 Date Revised 20.10.2021 published: Print-Electronic CommentIn: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):E190; author reply E191. - PMID 21169507 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1008256107 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM199853541 |
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| 245 | 1 | 0 | |a CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy |
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| 500 | |a CommentIn: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):E190; author reply E191. - PMID 21169507 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1alpha at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression | ||
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| 700 | 1 | |a Crudele, Valeria |e verfasserin |4 aut | |
| 700 | 1 | |a Giovane, Alfonso |e verfasserin |4 aut | |
| 700 | 1 | |a Casamassimi, Amelia |e verfasserin |4 aut | |
| 700 | 1 | |a Giordano, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Garban, Hermes J |e verfasserin |4 aut | |
| 700 | 1 | |a Cacciatore, Francesco |e verfasserin |4 aut | |
| 700 | 1 | |a Pentimalli, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Marquez-Garban, Diana C |e verfasserin |4 aut | |
| 700 | 1 | |a Petrillo, Antonella |e verfasserin |4 aut | |
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| 700 | 1 | |a Sommese, Linda |e verfasserin |4 aut | |
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| 700 | 1 | |a Siani, Alfredo |e verfasserin |4 aut | |
| 700 | 1 | |a Barbieri, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Arra, Claudio |e verfasserin |4 aut | |
| 700 | 1 | |a Rengo, Franco |e verfasserin |4 aut | |
| 700 | 1 | |a Hayashi, Toshio |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Omran, Mohammed |e verfasserin |4 aut | |
| 700 | 1 | |a Ignarro, Louis J |e verfasserin |4 aut | |
| 700 | 1 | |a Napoli, Claudio |e verfasserin |4 aut | |
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