TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies
Can Li, … , Ivana Frech, Fenghuang Zhan
Can Li, … , Ivana Frech, Fenghuang Zhan
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(14):e146893. https://doi.org/10.1172/JCI146893.
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Research Article Hematology

TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies

Abstract

Multiple myeloma (MM), a terminally differentiated B cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination, like ubiquitination, is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified, but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings suggest that TRIP13 expression plays a critical role in B cell lymphoma and MM by regulating deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, p53) proteins. High TRIP13 identifies a high-risk patient group amenable to adjuvant anti-USP7 therapy.

Authors

Can Li, Jiliang Xia, Reinaldo Franqui-Machin, Fangping Chen, Yanjuan He, Timothy Cody Ashby, Feixiang Teng, Hongwei Xu, Dingxiao Liu, Dongzheng Gai, Sarah K. Johnson, Frits van Rhee, Siegfried Janz, John D. Shaughnessy Jr., Guido Tricot, Ivana Frech, Fenghuang Zhan

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Figure 7

The USP7 inhibitor P5091 reduces TRIP13-induced BTZ drug resistance in MM.

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The USP7 inhibitor P5091 reduces TRIP13-induced BTZ drug resistance in M...
(A and B) ARP1 (A) and H929 (B) EV and TRIP13-OE cells treated with or without 10 nM BTZ or 10 μM P5091 alone or in combination for 48 hours followed by cell viability determination by trypan blue staining (n = 3 per condition). (C) ARP1 EV and TRIP13-OE cells (~0.5 × 106 cells per injection) were injected into the left and right flanks, respectively, of NSG mice. Mice were treated with vehicle control, BTZ (1 mg/kg, i.p., twice a week from day 7), P5091 (10 mg/kg, i.v., twice a week from day 3), and a combination. Mice were sacrificed and tumors were dissected and photographed by week 3 (n = 4 per group). (D and E) Tumor volume (D) and tumor weight (E) were measured and quantified from C. (F) TRIP13 gene expression signal is plotted on the y axis. Primary MM with TRIP13 expression in quartile 1 (n = 5) and quartile 4 (n = 5) and MM cell lines (MMCLs, n = 5) are grouped and plotted along the x axis. Corresponding TRIP13 and β-actin protein levels were analyzed from cell lysates of aliquot CD138-positive cells and MMCLs by Western blot. (G) TRIP13 gene expression signal of primary MM with low TRIP13 expression in quartile 1 (n = 6) and high TRIP13 expression in quartile 4 (n = 5) is plotted on the y axis. Corresponding CD138-positive cells were treated with or without 5 nM BTZ or 2.5 μM P5091 alone or in combination for 24 hours followed by cell viability determination by trypan blue staining. One high-TRIP13 sample was excluded because of low cell viability after thawing. Data are represented as mean ± SD. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 by Student’s t test in A and B and by Tukey’s test for multiplicity-adjusted P values in D, E, and G.