Abstract
Aurora kinases are serine/threonine kinases required for cell proliferation and are overexpressed in many human cancers. Targeting Aurora kinases has been a therapeutic strategy in cancer treatment. Here, we attempted to identify a deubiquitinase (DUB) that regulates Aurora kinase A (Aurora-A) protein stability and/or kinase activity as a potential cancer therapeutic target. Through pull-down assays with the human DUB library, we identified OTUD6A as an Aurora-A-specific DUB. OTUD6A interacts with Aurora-A through OTU and kinase domains, respectively, and deubiquitinates Aurora-A. Notably, OTUD6A promotes the protein half-life of Aurora-A and activates Aurora-A by increasing phosphorylation at threonine 288 of Aurora-A. From qPCR screening, we identified and validated that the cancer gene CKS2 encoding Cyclin-dependent kinases regulatory subunit 2 is the most upregulated cell cycle regulator when OTUD6A is overexpressed. The results suggest that OTUD6A may serve as a therapeutic target in human cancers.
Highlights
Aurora kinases are serine/threonine kinases required for cell proliferation
We found that OTUD6A deubiquitinates Aurora-A to stabilize and activate by interacting through the kinase domain of Aurora-A
We found that OTUD6A and Aurora-A interact with each other through their enzymatic domains, Ovarian tumor-associated proteases (OTUs) and kinase domains, respectively
Summary
Aurora kinases are serine/threonine kinases required for cell proliferation. Chromosomal missegregation during cell division causes genomic instability, contributing to carcinogenesis [1], and Aurora kinases play a role in proper chromosomal segregation. Aurora kinases are overexpressed in many human cancers including colorectal cancer, glioma, breast cancer, ovarian cancer, and pancreatic cancer [2,3,4,5,6,7], which has been driving an extensive investigation on their molecular functions in the cancer field and their roles as cancer targets in various human cancers. Targeting Aurora kinases is potentially an effective therapeutic strategy by eradicating cancer cells. Smallmolecule inhibitors targeting Aurora kinases including Aurora-A have been developed and tested in pre-clinical or clinical trials [18,19]
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