Hypoxia-Driven Ribosome Biogenesis: Unveiling a Novel Regulatory Role of HIF1α in Breast Cancer Progression and Metastasis [SUM1315_Hypoxia_RNA-seq]

Solid tumors such as breast cancer have intratumoral regions of low oxygen tension, which promotes cancer cell invasion and metastasis. Hypoxia-Inducible Factor 1-alpha (HIF1α) represents the principal transcription factor orchestrating cellular responses to hypoxic conditions, mediating the regulation of genes implicated in oxygen homeostasis. Here we describe our findings that demonstrate upregulation of RNA Polymerase I activity in cells exposed to hypoxic conditions. RNA Polymerase I is responsible for transcription of rDNA. Using confocal microscopy, we discovered that in hypoxia, HIF1ɑ localizes to the nucleolus, dependent on a previously unknown nucleolar localization signal in HIF1ɑ. Further detailed analysis by chromatin immunoprecipitation revealed that HIF1ɑ binds rDNA promoter at -230 and -350 bp. Ribosome biogenesis is important in supporting cellular metabolic processes and invasion and metastasis. Our analysis of publicly available data sets reveals that HIF1ɑ and rRNA biogenesis are upregulated in breast cancer patients and are associated with poor prognosis. Our studies show that inhibition of RNA Pol I diminished hypoxia-triggered invasion of breast cancer cells. Cumulatively our work unravels a novel role of HIF1ɑ in regulating rRNA biogenesis in breast cancer.