The deubiquitinase USP54 is overexpressed in colorectal cancer stem cells and promotes intestinal tumorigenesis

被引:27
作者
Fraile, Julia M. [1 ]
Campos-Iglesias, Diana [1 ]
Rodriguez, Francisco [1 ]
Espanol, Yaiza [1 ]
Freije, Jose M. P. [1 ]
机构
[1] Univ Oviedo, Inst Univ Oncol, Fac Med, Dept Bioquim & Biol Mol, Oviedo, Spain
关键词
degradome; CSCs; ubiquitin-specific proteases; gene targeting; PROTEASES; RELAPSE; DISEASE; SYSTEM; ROLES;
D O I
10.18632/oncotarget.12769
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Ubiquitin-Specific Proteases (USPs) are deubiquitinating enzymes frequently deregulated in human malignancies. Here, we show that USP54 is overexpressed in intestinal stem cells and demonstrate that its downregulation in colorectal carcinoma cells impedes tumorigenesis. We have generated mutant mice deficient for this deubiquitinase, which are viable and fertile, and protected against chemically-induced colorectal carcinoma. Furthermore, we show that USP54 is upregulated in human colon cancer and associates with poor prognosis. In agreement with these results, Usp54 downregulation in mouse melanoma cells inhibits lung metastasis formation. Collectively, this work has uncovered the pro-tumorigenic properties of USP54, highlighting the importance of deubiquitinating enzymes as promising targets for the development of specific anti-cancer therapies.
引用
收藏
页码:74427 / 74434
页数:8
相关论文
共 22 条
[11]   Inactivation of HAUSP in vivo modulates p53 function [J].
Kon, N. ;
Kobayashi, Y. ;
Li, M. ;
Brooks, C. L. ;
Ludwig, T. ;
Gu, W. .
ONCOGENE, 2010, 29 (09) :1270-1279
[12]   Proteases: Multifunctional Enzymes in Life and Disease [J].
Lopez-Otin, Carlos ;
Bond, Judith S. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (45) :30433-30437
[13]   Tumour micro environment -: Opinion -: Emerging roles of proteases in tumour suppression [J].
LOpez-Otin, Carlos ;
Matrisian, Lynn M. .
NATURE REVIEWS CANCER, 2007, 7 (10) :800-808
[14]   Proteolytic networks in cancer [J].
Mason, Steven D. ;
Joyce, Johanna A. .
TRENDS IN CELL BIOLOGY, 2011, 21 (04) :228-237
[15]   The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse [J].
Merlos-Suarez, Anna ;
Barriga, Francisco M. ;
Jung, Peter ;
Iglesias, Mar ;
Virtudes Cespedes, Maria ;
Rossell, David ;
Sevillano, Marta ;
Hernando-Momblona, Xavier ;
da Silva-Diz, Victoria ;
Munoz, Purificacion ;
Clevers, Hans ;
Sancho, Elena ;
Mangues, Ramon ;
Batlle, Eduard .
CELL STEM CELL, 2011, 8 (05) :511-524
[16]   Cloning and enzymatic analysis of 22 novel human ubiquitin-specific proteases [J].
Quesada, V ;
Díaz-Perales, A ;
Gutiérrez-Fernández, A ;
Garabaya, C ;
Cal, S ;
López-Otín, C .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 314 (01) :54-62
[17]   New roles for mitochondrial proteases in health, ageing and disease [J].
Quiros, Pedro M. ;
Langer, Thomas ;
Lopez-Otin, Carlos .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2015, 16 (06) :345-359
[18]   Transcriptome profile of human colorectal adenomas [J].
Sabates-Beliver, Jacob ;
Van der Flier, Laurens G. ;
de Palo, Mariagrazia ;
Cattaneo, Elisa ;
Maake, Caroline ;
Rehrauer, Hubert ;
Laczko, Endre ;
Kurowski, Michal A. ;
Bujnicki, Janusz M. ;
Menigatti, Mirco ;
Luz, Judith ;
Ranalli, Teresa V. ;
Gornes, Vito ;
Pastorelli, Alfredo ;
Faggiani, Roberto ;
Anti, Marcello ;
Jiricny, Josef ;
Clevers, Hans ;
Marra, Giancarlo .
MOLECULAR CANCER RESEARCH, 2007, 5 (12) :1263-1275
[19]   The tumor suppressor CYLD regulates entry into mitosis [J].
Stegmeier, Frank ;
Sowa, Mathew E. ;
Nalepa, Grzegorz ;
Gygi, Steven P. ;
Harper, J. Wade ;
Elledge, Stephen J. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (21) :8869-8874
[20]   The Importance of Ubiquitination and Deubiquitination in Cellular Reprogramming [J].
Suresh, Bharathi ;
Lee, Junwon ;
Kim, Kye-Seong ;
Ramakrishna, Suresh .
STEM CELLS INTERNATIONAL, 2016, 2016