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

doi:10.1016/j.chembiol.2017.03.002

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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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 language	English
Article number	e18
Pages (from-to)	458-470
Number of pages	13
Journal	Cell Chemical Biology
Volume	24
Issue number	4
Early online date	23 Mar 2017
DOIs	https://doi.org/10.1016/j.chembiol.2017.03.002
Publication status	Published - 20 Apr 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2017.03.002Licence: CC BY

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Copyright 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 6.54 MBLicence: CC BY

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Magiera, K., Tomala, M., Kubica, K., De Cesare, V., Trost, M., Zieba, B. J., Kachamakova-Trojanowska, N., Les, M., Dubin, G., Holak, T. A., & Skalniak, L. (2017). Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a. Cell Chemical Biology, 24(4), 458-470. Article e18. https://doi.org/10.1016/j.chembiol.2017.03.002

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

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.",

keywords = "USP2, lithocholic acid, colorectal carcinoma, cyclin D1, cell-cycle arrest, DUBs, ubiquitin-specific peptidase, non-competitive inhibitor",

author = "Katarzyna Magiera and Marcin Tomala and Katarzyna Kubica and {De Cesare}, Virginia and Matthias Trost and Zieba, {Bartosz J.} and Neli Kachamakova-Trojanowska and Marcin Les and Grzegorz Dubin and Holak, {Tad A.} and Lukasz Skalniak",

note = "Funding: MRC grant MC_UU_12016/5.",

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doi = "10.1016/j.chembiol.2017.03.002",

language = "English",

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journal = "Cell Chemical Biology",

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T1 - Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a

AU - Magiera, Katarzyna

AU - Tomala, Marcin

AU - Kubica, Katarzyna

AU - De Cesare, Virginia

AU - Trost, Matthias

AU - Zieba, Bartosz J.

AU - Kachamakova-Trojanowska, Neli

AU - Les, Marcin

AU - Dubin, Grzegorz

AU - Holak, Tad A.

AU - Skalniak, Lukasz

N1 - Funding: MRC grant MC_UU_12016/5.

PY - 2017/4/20

Y1 - 2017/4/20

N2 - 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.

AB - 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.

KW - USP2

KW - lithocholic acid

KW - colorectal carcinoma

KW - cyclin D1

KW - cell-cycle arrest

KW - DUBs

KW - ubiquitin-specific peptidase

KW - non-competitive inhibitor

U2 - 10.1016/j.chembiol.2017.03.002

DO - 10.1016/j.chembiol.2017.03.002

M3 - Article

C2 - 28343940

SN - 2451-9456

VL - 24

SP - 458

EP - 470

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 4

M1 - e18

ER -

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

Abstract

Keywords

UN SDGs

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