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

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

  • Cell Chem Biol. 2017 Apr 20;24(4):458-470.e18. doi: 10.1016/j.chembiol.2017.03.002.
Katarzyna Magiera 1,  Marcin Tomala 2,  Katarzyna Kubica 2,  Virginia De Cesare 3,  Matthias Trost 3,  Bartosz J Zieba 4,  Neli Kachamakova-Trojanowska 5,  Marcin Les 2,  Grzegorz Dubin 6,  Tad A Holak 1,  Lukasz Skalniak 7
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7a, 30-387 Krakow, Poland.
  • 2 Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Krakow, Poland.
  • 3 MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
  • 4 Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7a, 30-387 Krakow, Poland.
  • 5 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland.
  • 6 Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7a, 30-387 Krakow, Poland; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland.
  • 7 Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7a, 30-387 Krakow, Poland. Electronic address: lukasz.skalniak@uj.edu.pl.
PMID: 28343940 DOI: 10.1016/j.chembiol.2017.03.002
Abstract

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.

Keywords

DUBs; USP2; cell-cycle arrest; colorectal carcinoma; cyclin D1; lithocholic acid; non-competitive inhibitor; ubiquitin-specific peptidase.

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