Journal
ONCOGENE
Volume 40, Issue 37, Pages 5651-5664Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-01969-1
Keywords
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Funding
- WVUCI
- NIH [P20 RR016440, P30 RR032138/GM103488, P30GM103488, P30RR032138, RCP1101809, P20RR016440, U54GM104942, S10RR026378, GM104942, GM103434, OD016165, GM121322, P20GM103434, U54 GM-104942]
- NIH-NCI [CA148671]
- National Cancer Institute of the National Institutes of Health [CA148671]
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Metastatic breast cancer, especially in triple negative breast cancers, is a leading cause of breast cancer-related deaths. The presence of nuclear AURKA is molecularly connected to metastatic dissemination through HIF1 signaling, and it has been identified as a crucial driver of early metastasis. The expression of multiple HIF-dependent genes induced by nuclear AURKA promotes early cancer dissemination and is associated with decreased patient survival.
Metastatic breast cancer causes most breast cancer-associated deaths, especially in triple negative breast cancers (TNBC). The metastatic drivers of TNBCs are still poorly understood, and effective treatment non-existent. Here we reveal that the presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia-Inducible Factor-1) signaling. Nuclear AURKA activates transcription of hypoxia-induced genes under normoxic conditions (pseudohypoxia) and without upregulation of oxygen-sensitive HIF1A subunit. We uncover that AURKA preferentially binds to HIF1B and co-localizes with the HIF complex on DNA. The mass-spectrometry analysis of the AURKA complex further confirmed the presence of CBP and p300 along with other TFIIB/RNApol II components. Importantly, the expression of multiple HIF-dependent genes induced by nuclear AURKA (N-AURKA), including migration/invasion, survival/death, and stemness, promote early cancer dissemination. These results indicate that nuclear, but not cytoplasmic, AURKA is a novel driver of early metastasis. Analysis of clinical tumor specimens revealed a correlation between N-AURKA presence and decreased patient survival. Our results establish a mechanistic link between two critical pathways in cancer metastasis, identifying nuclear AURKA as a crucial upstream regulator of the HIF1 transcription complex and a target for anti-metastatic therapy.
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