Semester

Fall

Date of Graduation

2021

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Lori Hazlehurst

Committee Member

Scott Weed

Committee Member

Mike Ruppert

Committee Member

Tim Eubank

Committee Member

Sijin Wen

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.

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