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HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas

Oncogene volume 24, pages 3110–3120 (2005)Cite this article

Abstract

Hypoxia stimulates a number of pathways critical to cancer cell survival, including the activation of vascular endothelial growth factor (VEGF) transcription. In normal fibroblasts, hypoxia-induced activation of the protein tyrosine kinase, Src, is required for VEGF expression. We show here in both pancreatic and prostate carcinoma cell lines cobalt chloride (used to mimic hypoxia) -induced VEGF expression requires Src activation and leads to increased steady-state levels of HIF-1α and increased phosphorylation of signal and transducer of transcription 3 (STAT3). STAT3 and hypoxia-inducible factor (HIF)-1α bind simultaneously to the VEGF promoter, where they form a molecular complex with the transcription coactivators CBP/p300 and Ref-1/APE. Expression of activated Src from an inducible promoter is sufficient to increase VEGF expression and form these STAT3/HIF-1α-containing promoter complexes. Inhibition of DNA binding by expression of either STAT3 or HIF-1α dominant negative mutants significantly reduces VEGF expression. These data suggest that the binding of both STAT3 and HIF-1α to the VEGF promoter is required for maximum transcription of VEGF mRNA following hypoxia.

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Abbreviations

VEGF:

vascular endothelial growth factor

STAT3:

signal and transducer of transcription 3

HIF:

hypoxia inducible factor

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Acknowledgements

This work was supported by NIH 2RO-1 CA65527 and DOD PC020017 (GEG), NIH U54 CA 090810-01 (GEG and LME) and The Lockton Foundation (MJG, GEG, and LME); the Lustgarten Foundations (LME), and The American Hematological Association, Texas Affiliate (0455143Y) and The Gillson Longenbaugh Foundation (SSW). MJG is the Lockton Fellow for Pancreatic Cancer Research. We thank Dr James Darnell (The Rockefeller University) for the STAT-DN plasmid.

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Boulevard, Houston, TX, 77030, USA

    Michael J Gray, Jing Zhang, Lee M Ellis & Gary E Gallick

  2. The Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    Jing Zhang & Gary E Gallick

  3. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Boulevard, Houston, TX, 77030, USA

    Lee M Ellis & Douglas B Evans

  4. Vascular Program, Institute for Cell Engineering and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Gregg L Semenza

  5. Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Boulevard, Houston, TX, 77030, USA

    Stephanie S Watowich

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Correspondence to Gary E Gallick.

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Gray, M., Zhang, J., Ellis, L. et al. HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24, 3110–3120 (2005). https://doi.org/10.1038/sj.onc.1208513

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