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Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a

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.

Publication metadata

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


DOI: 10.1016/j.chembiol.2017.03.002

PubMed id: 28343940


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