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Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors

Authors :
Whately, Kristina M.
Voronkova, Maria A.
Maskey, Abha
Gandhi, Jasleen
Loskutov, Juergen
Choi, Hyeran
Yanardag, Sila
Chen, Dongquan
Wen, Sijin
Margaryan, Naira V.
Smolkin, Matthew B.
Purazo, Marc L.
Hu, Gangqing
Pugacheva, Elena N.
Source :
Oncogene; September 2021, Vol. 40 Issue: 37 p5651-5664, 14p
Publication Year :
2021

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.

Details

Language :
English
ISSN :
09509232 and 14765594
Volume :
40
Issue :
37
Database :
Supplemental Index
Journal :
Oncogene
Publication Type :
Periodical
Accession number :
ejs57264209
Full Text :
https://doi.org/10.1038/s41388-021-01969-1