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Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response

Author

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  • Zdenek Andrysik

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Heather Bender

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Matthew D. Galbraith

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Joaquin M. Espinosa

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus
    University of Colorado Boulder)

Abstract

Cellular adaptation to hypoxia is a hallmark of cancer, but the relative contribution of hypoxia-inducible factors (HIFs) versus other oxygen sensors to tumorigenesis is unclear. We employ a multi-omics pipeline including measurements of nascent RNA to characterize transcriptional changes upon acute hypoxia. We identify an immediate early transcriptional response that is strongly dependent on HIF1A and the kinase activity of its cofactor CDK8, includes indirect repression of MYC targets, and is highly conserved across cancer types. HIF1A drives this acute response via conserved high-occupancy enhancers. Genetic screen data indicates that, in normoxia, HIF1A displays strong cell-autonomous tumor suppressive effects through a gene module mediating mTOR inhibition. Conversely, in advanced malignancies, expression of a module of HIF1A targets involved in collagen remodeling is associated with poor prognosis across diverse cancer types. In this work, we provide a valuable resource for investigating context-dependent roles of HIF1A and its targets in cancer biology.

Suggested Citation

  • Zdenek Andrysik & Heather Bender & Matthew D. Galbraith & Joaquin M. Espinosa, 2021. "Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21687-2
    DOI: 10.1038/s41467-021-21687-2
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    1. Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Mary C. Bedard & Tafadzwa Chihanga & Adrean Carlile & Robert Jackson & Marion G. Brusadelli & Denis Lee & Andrew VonHandorf & Mark Rochman & Phillip J. Dexheimer & Jeffrey Chalmers & Gerard Nuovo & Ma, 2023. "Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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