NF-YA promotes invasion and angiogenesis by upregulating EZH2-STAT3 signaling in human melanoma cells

• Published in: Oncology reports Vol. 35; no. 6; pp. 3630 - 3638
• Main Authors: XU, ZIHAN, SUN, YAOWEN, GUO, YADONG, QIN, GAOPING, MU, SHENGZHI, FAN, RONGHUI, WANG, BENFENG, GAO, WENJIE, WU, HANGLI, WANG, GUODONG, ZHANG, ZHENXIN
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.06.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Angiogenesis; CCAAT-Binding Factor - metabolism; Cell adhesion & migration; Cell Line, Tumor; Cellular signal transduction; Chemotherapy; Cytokines; Development and progression; enhancer of zeste homolog 2; Enhancer of Zeste Homolog 2 Protein - metabolism; Gene expression; Genetic aspects; Health aspects; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Melanoma; Melanoma - pathology; Methods; Methylation; Molecular targeted therapy; Neoplasm Invasiveness - pathology; Neovascularization, Pathologic - pathology; nuclear transcription factor-Y alpha; Phosphorylation; Plasmids; Properties; Proteins; Signal Transduction; STAT3; STAT3 Transcription Factor - metabolism; Transcription factors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - secretion; United States > US
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2016.4761

The process of angiogenesis is essential for tumor development and metastasis. Vascular endothelial growth factor (VEGF), which is overexpressed in most human cancers, has been demonstrated to be a major modulator of angiogenesis. Thus, inhibition of VEGF signaling has the potential for tumor anti-angiogenic therapy. Signal transducer and activator of transcription-3 (STAT3) is a key regulator for angiogenesis by directly binding to the VEGF promoter to upregulate its transcription. Several factors can enhance STAT3 activity to affect angiogenesis. Here, we found that overexpression of nuclear transcription factor-Y alpha (NF-YA) gene could promote cell invasion and angiogenesis accompanying the increase of STAT3 signaling in human melanoma cells. Moreover, the expression and secretion of VEGF was also found to be upregulated by the overexpression of NF-YA gene in melanoma cells. The STAT3 inhibitor was able to attenuate the upregulation of VEGF induced by NF-YA overexpression. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, enhances STAT3 activity by mediating its lysine methylation. We also showed that NF-YA upregulated the expression of EZH2 and NF-YA-induced angiogenesis could be inhibited by EZH2 knockdown. Taken together, these findings indicate that overexpression of NF-YA contributes to tumor angiogenesis through EZH2-STAT3 signaling in human melanoma cells, highlighting NF-YA as a potential therapeutic target in human melanoma.