1. Nuclear Aurora-A kinase-induced hypoxia signaling drives dissemination and metastasis in breast cancer.
- Author
-
Whately, Kristina Marinak
- Subjects
- cancer biology, Aurora-A Kinase, AURKA, metastasis, breast cancer, nuclear AURKA, Cancer Biology, Cell Biology
- Abstract
Metastatic breast cancer causes the vast majority of cancer-associated deaths, especially in triple negative breast cancers (TNBC). TNBC is still poorly understood and has no effective treatment. Here we reveal that presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia induced factor-1) signaling. The nuclear AURKA in the complex with constitutively expressed HIF-1β subunit activates transcription of “hypoxia induced genes” under normoxic conditions (the phenomenon called pseudohypoxia) without upregulation of oxygen-sensitive HIF-1α subunit. We uncover that AURKA preferentially binds to and phosphorylates HIF-1β, and co-localizes with HIF complex on DNA. The mass spectrometry analysis of AURKA complex further confirmed presence of CBP and p300 along with other TFIIB/RNApol II components. Importantly, expression of multiple HIF-dependent genes including migration/invasion, survival/death and stemness induced by nuclear AURKA promote early cancer dissemination. These results indicate that nuclear pool of AURKA, but not cytoplasmic, is a novel driver of early metastatic dissemination. Analysis of clinical tumor specimens revealed a correlation between HIF- 1α and AURKA levels and an association of their co-expression to decreased patient survival. Our results establish a mechanistic linkage between two key pathways in cancer metastasis, identifying nuclear AURKA as a critical upstream regulator of HIF-1 transcription complex, and a target for anti-metastatic therapy.
- Published
- 2021