CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy

Filomena De Nigris, Valeria Crudele, Alfonso Giovane, Amelia Casamassimi, Antonio Giordano, Hermes J. Garban, Francesco Cacciatore, Francesca Pentimalli, Diana C. Marquez-Garban, Antonella Petrillo, Letizia Cito, Linda Sommese, Andrea Fiore, Mario Petrillo, Alfredo Siani, Antonio Barbieri, Claudio Arra, Franco Rengo, Toshio Hayashi, Mohammed Al-OmranLouis J. Ignarro, Claudio Napoli

Research output: Contribution to journalArticle

Abstract

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-1α 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.

Original languageEnglish
Pages (from-to)14484-14489
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number32
DOIs
Publication statusPublished - Aug 10 2010

Keywords

  • Cancer
  • Metastasis
  • Oncogene

ASJC Scopus subject areas

  • General

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  • Cite this

    De Nigris, F., Crudele, V., Giovane, A., Casamassimi, A., Giordano, A., Garban, H. J., Cacciatore, F., Pentimalli, F., Marquez-Garban, D. C., Petrillo, A., Cito, L., Sommese, L., Fiore, A., Petrillo, M., Siani, A., Barbieri, A., Arra, C., Rengo, F., Hayashi, T., ... Napoli, C. (2010). CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proceedings of the National Academy of Sciences of the United States of America, 107(32), 14484-14489. https://doi.org/10.1073/pnas.1008256107