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.
de Nigris
Filomena
F
Division of Clinical Pathology, Department of General Pathology, School of Medicine, Second University of Naples, 80138 Naples, Italy.
Crudele
Valeria
V
Giovane
Alfonso
A
Casamassimi
Amelia
A
Giordano
Antonio
A
Garban
Hermes J
HJ
Cacciatore
Francesco
F
Pentimalli
Francesca
F
Marquez-Garban
Diana C
DC
Petrillo
Antonella
A
Cito
Letizia
L
Sommese
Linda
L
Fiore
Andrea
A
Petrillo
Mario
M
Siani
Alfredo
A
Barbieri
Antonio
A
Arra
Claudio
C
Rengo
Franco
F
Hayashi
Toshio
T
Al-Omran
Mohammed
M
Ignarro
Louis J
LJ
Napoli
Claudio
C
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D042442:Vascular Endothelial Growth Factors / Q000235:genetics*; D050986:YY1 Transcription Factor / Q000378:metabolism* / Q000502:physiology
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010455:Peptides; D019718:Receptors, CXCR4; C516580:T22 peptide; D014157:Transcription Factors; D042442:Vascular Endothelial Growth Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human