Regulation of KIFC1 expression and centrosome clustering by deubiquitylases (360G-Wellcome-109307_Z_15_A)
KIFC1 (HSET) is a minus-end-directed kinesin whose depletion promotes multipolar mitosis in cancer cells carrying additional centrosomes. Centrosome amplification often occurs in breast and ovarian cancers where KIFC1 is also frequently overexpressed. While cancer cells usually overcome the presence of additional centrosomes by clustering them into two groups to form pseudo-bipolar spindles, they lose this ability in the absence of KIFC1. As multipolar mitosis is usually lethal, targeting KIFC1 may selectively kill cancer cells without affecting non-transformed cells. This exciting hypothesis currently lacks systematic validation. Here, the KIFC1 requirement for normal mitosis and survival will be addressed in a panel of cancer and non-transformed cell lines. Stability of proteins in cells may be regulated by a family of ~90 deubiquitylase (DUB) enzymes, which recently aroused interest as potential drug targets. Targeting a DUB that stabilizes KIFC1 would be predicted to promote KIFC1 degradation and multipolar mitosis. In this project we will identify DUBs that maintain cellular levels of KIFC1, then characterize the effect of their depletion and their mechanistic interaction with KIFC1. Lastly, we will assess the clinical relevance of our findings, by evaluating expression of KIFC1 and its regulatory DUBs in breast cancer patient tissues and performing clinicopathological correlations.
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