USP39 Deubiquitinase Is Essential for Oncogene-driven Cancer

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Feb 4

PMID 28154181

Citations 28

Authors

Julia M Fraile

Eusebio Manchado

Amaia Lujambio

Victor Quesada

Diana Campos-Iglesias

Thomas R Webb

Scott W Lowe

Carlos Lopez-Otin

Jose M P Freije

Affiliations

Soon will be listed here.

Abstract

is the most frequently mutated oncogene in human cancer, but its therapeutic targeting remains challenging. Here, we report a synthetic lethal screen with a library of deubiquitinases and identify , which encodes an essential splicing factor, as a critical gene for the viability of KRAS-dependent cells. We show that splicing fidelity inhibitors decrease preferentially the proliferation rate of KRAS-active cells. Moreover, depletion of , encoding an USP39-interacting splicing factor, also reduces the viability of these cells. In agreement with these results, USP39 depletion caused a significant reduction in pre-mRNA splicing efficiency, as demonstrated through RNA-seq experiments. Furthermore, we show that is up-regulated in lung and colon carcinomas and its expression correlates with levels and poor clinical outcome. Accordingly, our work provides critical information for the development of splicing-directed antitumor treatments and supports the potential of USP39-targeting strategies as the basis of new anticancer therapies.

Citing Articles

The Clinical Prediction Value of the Ubiquitination Model Reflecting the Microenvironment Infiltration and Drug Sensitivity in Breast Cancer.

Ma H, Cao J, Zhang Y, Yang J, Wang X, Yu Y J Cancer. 2025; 16(3):784-801.

PMID: 39781342 PMC: 11705054. DOI: 10.7150/jca.101525.

Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation.

Sirera J, Sarlak S, Teisseire M, Carminati A, Nicolini V, Savy C J Exp Clin Cancer Res. 2024; 43(1):335.

PMID: 39736693 PMC: 11686864. DOI: 10.1186/s13046-024-03241-2.

Mapping and visualization of global research progress on deubiquitinases in ovarian cancer: a bibliometric analysis.

Qiu F, Li Y, Zhou L, Wu Y, Wu Y, Fan Z Front Pharmacol. 2024; 15:1445037.

PMID: 39329115 PMC: 11424541. DOI: 10.3389/fphar.2024.1445037.

USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells.

Gao B, Qiao Y, Zhu S, Yang N, Zou S, Liu Y J Biol Chem. 2024; 300(7):107463.

PMID: 38876304 PMC: 11268115. DOI: 10.1016/j.jbc.2024.107463.

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review.

Al-Balushi E, Al Marzouqi A, Tavoosi S, Baghsheikhi A, Sadri A, Sharifi Aliabadi L World J Gastrointest Oncol. 2024; 16(1):197-213.

PMID: 38292842 PMC: 10824112. DOI: 10.4251/wjgo.v16.i1.197.

References

Zhang C, Cai T, Zhu H, Yang L, Jiang H, Dong X . Synergistic antitumor activity of gemcitabine and ABT-737 in vitro and in vivo through disrupting the interaction of USP9X and Mcl-1. Mol Cancer Ther. 2011; 10(7):1264-75. DOI: 10.1158/1535-7163.MCT-10-1091. View

Lopez-Otin C, Hunter T . The regulatory crosstalk between kinases and proteases in cancer. Nat Rev Cancer. 2010; 10(4):278-92. DOI: 10.1038/nrc2823. View

Kumar M, Hancock D, Molina-Arcas M, Steckel M, East P, Diefenbacher M . The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell. 2012; 149(3):642-55. DOI: 10.1016/j.cell.2012.02.059. View

van Leuken R, Luna-Vargas M, Sixma T, Wolthuis R, Medema R . Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B. Cell Cycle. 2008; 7(17):2710-9. DOI: 10.4161/cc.7.17.6553. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Shirasawa S, Furuse M, Yokoyama N, Sasazuki T . Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science. 1993; 260(5104):85-8. DOI: 10.1126/science.8465203. View

Corrionero A, Minana B, Valcarcel J . Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev. 2011; 25(5):445-59. PMC: 3049286. DOI: 10.1101/gad.2014311. View

Cox A, Fesik S, Kimmelman A, Luo J, Der C . Drugging the undruggable RAS: Mission possible?. Nat Rev Drug Discov. 2014; 13(11):828-51. PMC: 4355017. DOI: 10.1038/nrd4389. View

Hegele A, Kamburov A, Grossmann A, Sourlis C, Wowro S, Weimann M . Dynamic protein-protein interaction wiring of the human spliceosome. Mol Cell. 2012; 45(4):567-80. DOI: 10.1016/j.molcel.2011.12.034. View

10.

Bonnal S, Vigevani L, Valcarcel J . The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov. 2012; 11(11):847-59. DOI: 10.1038/nrd3823. View

11.

Webb T, Joyner A, Potter P . The development and application of small molecule modulators of SF3b as therapeutic agents for cancer. Drug Discov Today. 2012; 18(1-2):43-9. PMC: 3596818. DOI: 10.1016/j.drudis.2012.07.013. View

12.

Solimini N, Luo J, Elledge S . Non-oncogene addiction and the stress phenotype of cancer cells. Cell. 2007; 130(6):986-8. DOI: 10.1016/j.cell.2007.09.007. View

13.

Steckel M, Molina-Arcas M, Weigelt B, Marani M, Warne P, Kuznetsov H . Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res. 2012; 22(8):1227-45. PMC: 3411175. DOI: 10.1038/cr.2012.82. View

14.

Torrance C, Agrawal V, Vogelstein B, Kinzler K . Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nat Biotechnol. 2001; 19(10):940-5. DOI: 10.1038/nbt1001-940. View

15.

Weinstein I, Joe A . Mechanisms of disease: Oncogene addiction--a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006; 3(8):448-57. DOI: 10.1038/ncponc0558. View

16.

Eichhorn P, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E . USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med. 2012; 18(3):429-35. DOI: 10.1038/nm.2619. View

17.

Singh A, Sweeney M, Yu M, Burger A, Greninger P, Benes C . TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell. 2012; 148(4):639-50. PMC: 3291475. DOI: 10.1016/j.cell.2011.12.033. View

18.

Sowa M, Bennett E, Gygi S, Harper J . Defining the human deubiquitinating enzyme interaction landscape. Cell. 2009; 138(2):389-403. PMC: 2716422. DOI: 10.1016/j.cell.2009.04.042. View

19.

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

20.

Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N . A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009; 15(6):489-500. PMC: 2743093. DOI: 10.1016/j.ccr.2009.03.022. View