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

Katarzyna Magiera, Marcin Tomala, Katarzyna Kubica, Virginia De Cesare, Matthias Trost, Bartosz J. Zieba, Neli Kachamakova-Trojanowska, Marcin Les, Grzegorz Dubin, Tad A. Holak, Lukasz Skalniak (Lead / Corresponding author)

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18 Citations (Scopus)
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Abstract

USP2a is a deubiquitinase responsible for stabilization of cyclin D1 – a crucial regulatorbof 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, 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, both p53-expressing and p53-defective cancer types.
Original languageEnglish
Article numbere18
Pages (from-to)458-470
Number of pages13
JournalCell Chemical Biology
Volume24
Issue number4
Early online date23 Mar 2017
DOIs
Publication statusPublished - 20 Apr 2017

Keywords

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

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