Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells

Biochemical and Biophysical Research Communications
Gibok LeeJi-Hong Lim

Abstract

USP7 is a deubiquitinating enzyme that involves the ubiquitin proteasome system (UPS) to maintain regulation of protein synthesis and degradation. The well-known substrate of USP7 is the Mdm2-p53 complex. In fact, several studies have reported that functional inhibition of USP7 induces cancer cell apoptosis through activation of p53. However, the contribution of oxidative or endoplasmic reticulum (ER) stress, which is commonly induced by inhibition of the UPS for USP7 inhibitor-mediated apoptosis in cancer cells, has not been investigated. In contrast to previous reports, we show that p53 is not critical during USP7 inhibitor-induced apoptosis in several cancer cells. Inhibition of deubiquitinating enzyme activities by USP7 inhibitors causes ER stress by accumulating polyubiquitinated proteins in cancer cells. Furthermore, we demonstrate that USP7 inhibitors increase intracellular reactive oxygen species and mainly cause cancer cell apoptosis. Taken together, our results reveal that oxidative and ER stress, rather than the Mdm2-p53 axis, mainly contributes to USP7 inhibitor-mediated apoptosis in cancer cells.

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Citations

May 18, 2016·Journal of Structural Biology·Robbert Q KimTitia K Sixma
Oct 19, 2017·Nature·Andrew P TurnbullDavid Komander
Mar 27, 2020·Scientific Reports·Nathan J SchauerSara J Buhrlage
Mar 3, 2021·Journal of Veterinary Internal Medicine·Aleksandra PawlakVeronique A J Smits
Nov 7, 2020·Drug Discovery Today·Lauraine NininahazweZhe-Sheng Chen
Apr 9, 2020·Mutation Research. Genetic Toxicology and Environmental Mutagenesis·Laure KhouryMarc Audebert
May 1, 2021·International Journal of Molecular Sciences·Choong-Sil LeeJaewhan Song
May 1, 2021·International Journal of Molecular Sciences·Shiyao ChenHuchen Zhou

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