Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1Arrest by Inhibiting Deubiquitinase USP2a.
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.
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.
Katarzyna
K
Magiera
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Krakow, Poland.
Marcin
M
Tomala
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Krakow, Poland.
Katarzyna
K
Kubica
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Virginia
V
De Cesare
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Matthias
M
Trost
Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7a, 30-387 Krakow, Poland.
Bartosz J
BJ
Zieba
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland.
Neli
N
Kachamakova-Trojanowska
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Krakow, Poland.
Marcin
M
Les
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.
Grzegorz
G
Dubin
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.
Tad A
TA
Holak
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.
Lukasz
L
Skalniak
D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003513:Cycloheximide / Q000737:chemistry / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D061986:MCF-7 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008095:Lithocholic Acid; D003513:Cycloheximide; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase
DUBs; USP2; cell-cycle arrest; colorectal carcinoma; cyclin D1; lithocholic acid; non-competitive inhibitor; ubiquitin-specific peptidase