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Lookup NU author(s): Professor Matthias TrostORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types.
Author(s): Magiera K, Tomala M, Kubica K, De Cesare V, Trost M, Zieba BJ, Kachamakova-Trojanowska N, Les M, Dubin G, Holak TA, Skalniak L
Publication type: Article
Publication status: Published
Journal: Cell Chemical Biology
Year: 2017
Volume: 24
Issue: 4
Pages: 458-470.e18
Print publication date: 20/04/2017
Online publication date: 23/03/2017
Acceptance date: 01/03/2017
Date deposited: 06/06/2017
ISSN (electronic): 2451-9456
Publisher: Cell Press
URL: https://doi.org/10.1016/j.chembiol.2017.03.002
DOI: 10.1016/j.chembiol.2017.03.002
PubMed id: 28343940
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