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Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4

Oncogene volume 30, pages 2570–2580 (2011)Cite this article

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a principal regulator of angiogenesis and other cellular responses to hypoxic stress in both normal and tumor cells. To identify novel mechanisms that regulate expression of HIF-1α, we designed a genome-wide screen for expressed sequence tags (ESTs) that when transcribed in the antisense direction increase production of the HIF-1α target, vascular endothelial growth factor (VEGF), in human breast cancer cells. We discovered that heat shock factor (HSF) proteins 2 and 4—which previously have been implicated in the control of multiple genes that modulate cell growth and differentiation and protect against effects of environmental and cellular stresses—function together to maintain a steady state level of HIF-1α transcription and VEGF production in these cells. We show both HSFs bind to discontinuous heat shock element (HSE) sequences we identified in the HIF-1α promoter region and that downregulation of either HSF activates transcription of HIF-1α. We further demonstrate that HSF2 and HSF4 displace each other from HSF/HSE complexes in the HIF-1α promoter so that HIF-1α transcription is also activated by overexpression of either HSFs. These results argue that HSF2 and HSF4 regulate transcription of HIF-1α and that a critical balance between these HSF is required to maintain HIF-α expression in a repressed state. Our findings reveal a previously unsuspected role for HSFs in control of VEGF and other genes activated by canonical HIF-1α-mediated signaling.

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Acknowledgements

The study was supported by funds from the Kwoh-Ting Li Professorship to SNC, and by a grant from the National Foundation for Cancer Research (NFCR) to SNC.

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Author notes

  1. P E Kowalski

    Present address: 3Current address: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1L7.,

  2. Q Lu

    Present address: 4Current address: Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.,

Authors and Affiliations

  1. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA

    R Chen, J E Liliental, P E Kowalski, Q Lu & S N Cohen

  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    S N Cohen

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Correspondence to S N Cohen.

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Chen, R., Liliental, J., Kowalski, P. et al. Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4. Oncogene 30, 2570–2580 (2011). https://doi.org/10.1038/onc.2010.623

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