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• W2074584135 abstract "Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation.Background: VEGF plays an important role in tumor growth and metastasis.Results: KLF-4 suppresses VEGF expression in normal breast cells by recruiting HDACs. Cancer cells do not recruit HDACs due to low KLF-4 levels.Conclusion: Loss of KLF-4-HDAC-mediated suppression and active recruitment of SAF-1 causes cancer cell-specific VEGF expression.Significance: Findings identified a previously unknown mechanism of VEGF regulation and revealed new therapeutic targets. Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation. Background: VEGF plays an important role in tumor growth and metastasis. Results: KLF-4 suppresses VEGF expression in normal breast cells by recruiting HDACs. Cancer cells do not recruit HDACs due to low KLF-4 levels. Conclusion: Loss of KLF-4-HDAC-mediated suppression and active recruitment of SAF-1 causes cancer cell-specific VEGF expression. Significance: Findings identified a previously unknown mechanism of VEGF regulation and revealed new therapeutic targets." @default.
• W2074584135 created "2016-06-24" @default.
• W2074584135 creator A5020111511 @default.
• W2074584135 creator A5023928408 @default.
• W2074584135 creator A5066190212 @default.
• W2074584135 date "2013-09-01" @default.
• W2074584135 modified "2023-10-16" @default.
• W2074584135 title "Loss of Epigenetic Kruppel-like Factor 4 Histone Deacetylase (KLF-4-HDAC)-mediated Transcriptional Suppression Is Crucial in Increasing Vascular Endothelial Growth Factor (VEGF) Expression in Breast Cancer" @default.
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• W2074584135 doi "https://doi.org/10.1074/jbc.m113.481184" @default.
• W2074584135 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3779720" @default.
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• W2074584135 hasPublicationYear "2013" @default.
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