Article ; Online: Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors.
2021 Volume 40, Issue 37, Page(s) 5651–5664
Abstract: 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 ...
| Abstract | 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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| MeSH term(s) | Aurora Kinase A ; Cell Communication ; Cell Nucleus ; E1A-Associated p300 Protein ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; Signal Transduction ; Triple Negative Breast Neoplasms | |||||
| Chemical Substances | HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; E1A-Associated p300 Protein (EC 2.3.1.48) ; EP300 protein, human (EC 2.3.1.48) ; Aurora Kinase A (EC 2.7.11.1) | |||||
| Language | English | |||||
| Publishing date | 2021-07-29 | |||||
| Publishing country | England | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural | |||||
| ZDB-ID | 639046-8 | |||||
| ISSN | 1476-5594 ; 0950-9232 | |||||
| ISSN (online) | 1476-5594 | |||||
| ISSN | 0950-9232 | |||||
| DOI | 10.1038/s41388-021-01969-1 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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