Hypoxic stress incites HIF1α-driven ribosome biogenesis that can be exploited by targeting RNA Polymerase I

Amr Elhamamsy, Brandon J. Metge, Courtney A. Swain, Mohamed H. Elbahoty, Dominique C. Hinshaw, Sarah C. Kammerud, Dongquan Chen, Rajeev S. Samant () and Lalita A. Shevde ()
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Amr Elhamamsy: University of Alabama at Birmingham
Brandon J. Metge: University of Alabama at Birmingham
Courtney A. Swain: University of Alabama at Birmingham
Mohamed H. Elbahoty: University of Alabama at Birmingham
Dominique C. Hinshaw: University of Alabama at Birmingham
Sarah C. Kammerud: University of Alabama at Birmingham
Dongquan Chen: University of Alabama at Birmingham
Rajeev S. Samant: University of Alabama at Birmingham
Lalita A. Shevde: University of Alabama at Birmingham

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Intratumoral low oxygen tension promotes cancer cell invasion and metastasis. Hypoxia-Inducible Factor 1-alpha (HIF1α) is the principal transcription factor orchestrating cellular responses to hypoxic stress, mediating the regulation of genes implicated in adapting to perturbations in oxygen homeostasis. Here, we describe our findings that functionally demonstrate a nucleolar localization domain in HIF1ɑ that enables HIF1ɑ to translocate to the nucleolus. Nucleolar HIF1ɑ binds the ribosomal DNA promoter and upregulates RNA Polymerase I activity leading to dysregulated ribosomal RNA transcription and consequently enhanced ribosome biogenesis. Ribosome biogenesis is important in supporting cellular metabolic processes and invasion and metastasis. Our findings are recapitulated in breast tumors wherein upregulated HIF1ɑ and rRNA biogenesis are associated with poor prognosis. Finally, our studies demonstrate that inhibition of RNA Polymerase I impedes aggressive traits of hypoxia-driven cancer progression, highlighting the potential of this approach as a therapeutic strategy in breast cancer. Cumulatively our work unravels an unprecedented role of HIF1ɑ in regulating rRNA biogenesis in breast cancer.

Date: 2025
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DOI: 10.1038/s41467-025-63315-3

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